TW202120543A - Personalized treatment of ophthalmologic diseases - Google Patents

Abstract

The current invention relates to antibodies which bind to VEGF and ANG2 for use in the treatment of ocular vascular diseases such as neovascular AMD (nAMD) (also known as choroidal neovascularization [CNV] secondary to age-related macular degeneration [AMD] or wet AMD), diabetic retinopathy in particular diabetic macular edema (DME) or macular edema secondary to retinal vein occlusion (RVO).

Description

Personalized treatment of eye diseases

The present invention relates to antibodies that bind to VEGF and ANG2 for the treatment of ocular vascular diseases, such as neovascular AMD (nAMD) (also known as choroidal secondary to age-related macular degeneration [AMD] or wet AMD Neovascularization [CNV]), diabetic retinopathy, specifically diabetic macular edema (DME) or macular edema secondary to retinal vein occlusion (RVO).

Such as neovascular AMD (nAMD) (also known as choroidal neovascularization secondary to age-related macular degeneration [AMD] or wet AMD [CNV], diabetic retinopathy (specifically, diabetic macular edema (DME)) ) Ocular vascular disease is a serious disease that often causes vision loss and blindness.

Neovascular age-related macular degeneration (nAMD) (also known as choroidal neovascularization secondary to age-related macular degeneration [AMD] or wet AMD [CNV]) is an advanced form of AMD that causes rapid and severe vision loss and It is still the main cause of visual impairment in the elderly (Bourne et al., Lancet Glob Health 2013; 1:e339-49; Wong et al., Lancet Glob Health 2014; 2:e106-16). Several biochemical and biological processes such as angiogenesis, inflammation, and oxidative stress are known to play a role in the pathogenesis of nAMD, which is characterized by abnormal proliferation of choroidal capillaries, which penetrate Bruch's membrane and Transfer to or through the retinal pigment epithelium. If left untreated, CNV allows fluid, lipids, and blood to leak into the outer retina, causing severe and irreversible loss of central vision.

Before anti-vascular endothelial growth factor (anti-VEGF) agents, laser photocoagulation therapy and photodynamic therapy using verteporfin were the standard of care and demonstrated to stabilize vision. Although this type of treatment is still a therapeutic option for selected patients, nAMD treatment has been significantly improved by introducing biomolecules that target VEGF-A, an important factor in pathological angiogenesis (Brown et al., N Engl J Med 2006;355:1432-44; Rosenfeld et al., N Engl J Med 2006;355:1419-31; Heier et al., Ophthalmology 2012;119:2537-48). Since the first approval of Lucentis® (ranibizumab) in 2006, the impressive benefits of anti-VEGF therapy and its ability to restore vision have been widely recognized (American Academy of Ophthalmology 2015).

The key challenge of currently available anti-VEGF treatments is the need for frequent and long-term administration to maintain vision growth (Heier et al., Ophthalmology 2012;119:2537-48; the Comparison of Age-Related Macular Degeneration Treatment Trials [CATT] Research Group 2016 Ophthalmology 2016;123:1751-61). Real-world data indicate that many patients with nAMD are not treated at the optimal frequency, and compared with those observed in controlled clinical trials, this inadequate treatment in clinical practice is associated with lower visual acuity (VA) growth (Cohen et al., Retina 2013;33:474-81; Finger et al., Acta Ophthalmol 2013;91:540-6; Holz et al., Br J Ophthalmol 2015;99:220-6; Rao et al., Ophthalmology 2018; 125:522-28). Insufficient treatment of nAMD in clinical practice reflects the burden of frequent therapy on patients, caregivers and medical systems (Gohil et al., PLoS One 2015;10:e0129361; Prenner et al., Am J Ophthalmol 2015;160:725-31; Varano et al. Human, Clin Ophthalmol 2015;9:2243-50; CATT Research Group et al., Ophthalmology 2016;123:1751-61; Vukicevic et al., Eye 2016;30: 413-21).

Diabetic macular edema (DME), a complication of diabetic retinopathy (DR), may appear at any stage of the underlying disease of retinal capillaries (Fong et al., Diabetes Care 2004;27:2540-53). As potential DR deteriorates from non-proliferative DR (NPDR) to proliferative DR (PDR), the frequency of DME increases (Henricsson et al., Acta Ophthalmol. Scand. 1999: 77: 218-223; Johnson Am J Ophthalmol 2009; 147:11-21). DME is the most common cause of moderate and severe visual impairment in patients with DR (Ciulla et al., Diabetes Care 2003;26:2653-64; Davidson et al., Endocrine 2007;32:107-16;Leasher et al., Diabetes Care 2016;39:1643-9), and if left untreated, it may cause about 50% of patients to lose 10 or more letters of vision (VA) within 2 years (Ferris and Patz Surv Ophthamol 1984; 28 Supplement:452- 61; Diabetes Care 2003;26:2653-64 et al., 2003). DME affects approximately 14% of patients with diabetes and can be found in patients with both type 1 and type 2 diabetes (Girach and Lund-Andersen Int J Clin Practice 2007; 61: 88-97). In 2013, the world's population with diabetes was approximately 382 million, and it is estimated that by 2035, it will increase to 592 million (International Diabetes Federation 2013).

With the development of imaging technology, DME is now often diagnosed by optical coherent tomography (OCT) instead of based on the traditional early treatment of diabetic retinopathy (ETDRS) ophthalmoscope. At the molecular level, DME is the result of vascular endothelial growth factor-A (VEGF-A)-mediated increase in vascular permeability and loss of outer cover cells. It promotes angiogenesis, high permeability and promotes hypoxia mediated by hypoxia. Caused by the release of inflammatory mediators (Antonetti et al., Semin Ophthalmol 1999; 14:240-8). VEGF also up-regulates the stability factor Angiopoietin-2 (Ang-2), which acts as an antagonist of Tie2 receptor tyrosine kinase on endothelial cells, thereby resisting vascular stability maintained by Ang-1-dependent Tie2 activation . Therefore, Ang-2 acts as a vascular instability factor, thereby making the vascular structure more elastic and prone to rupture and sprouting of the endothelial barrier. Excessive Ang-2 and VEGF in retinal tissue promote vascular instability, vascular leakage and new blood vessel formation. Ang-2 is also involved in inflammatory pathways, such as lymphocyte recruitment. In general, both VEGF-A and Ang-2 are recognized as key factors that mediate the pathogenesis of diabetic eye disease (Aiello et al., N Engl J Med 1994;331:1480-7; Davis et al., Cell 1996;87 :1161-9; Maisonpierre et al., Science 1997;277:55-60; Gardner et al., Surv Ophthalmol 2002;47(Supplement 2):S253-62; Joussen et al., Am J Path 2002;160:501-9 ; Fiedler et al., J Biol Chem 2003;278:1721-7).

Although macular lasers are used as the standard of care (SOC) for the treatment of DME, the development of anti-VEGF drug therapies in the past 10 years has caused significant improvements in the visual outcomes of patients suffering from DME. Currently available anti-VEGF therapies for DME include lambizumab and aflibercept. Other approved options available for the treatment of DME include periocular or intravitreal (IVT) steroids and steroid implants.

Although anti-VEGF therapy has achieved strong efficacy in DME, in the real world, a larger proportion of patients have not experienced clinically meaningful vision improvement. Frequent IVT administration is required to achieve and in some cases maintain the observed benefits of early DME treatment over a longer period of time. The current SOC for administration of anti-VEGF injections requires patients to undergo frequent clinical examinations and IVT injections. This places a significant burden on patients, caregivers, treating physicians, and the medical system.

A large phase III trial of anti-VEGF agents in DME confirmed that after the first year of treatment, the number of injections required to maintain vision growth can be reduced (Diabetic Retinopathy Clinical Research Network et al., Ophthalmology 2010:117:1064-77. Electronic version : April 28, 2010; Schmidt-Erfurth et al., Ophthalmology 2014; 121:193-201; Elman et al., Ophthalmology 2015; 122:375-81). However, in order to achieve the best results in the absence of validated predictive biomarkers of treatment frequency, the standard anti-VEGF method of DME still relies on frequent monitoring visits and imposes a large burden on patients and medical providers. In addition, anti-VEGF monotherapy does not completely solve other pathways that contribute to the exacerbation of diabetic eye disease, including inflammation and instability of outer skin cells.

New treatments that target additional pathways and reduce the burden of IVT injections are needed to address the highly unmet medical needs in DME.

According to one aspect of the present invention, there are provided methods, uses, bispecific antibodies (for use), drugs or pharmaceutical formulations for treating patients suffering from ocular vascular diseases, the ocular vascular diseases selected from neovascular AMD (nAMD) and diabetic macular edema (DME), the method includes administering to the patient an effective amount of a combination of human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG -2) The bispecific antibody, wherein the treatment of patients suffering from ocular vascular disease (selected from nAMD and DME) includes prolonging the dosing interval in the case of stable absence of the disease or shortening the interval in the case of disease activity Medicine schedule. In this way, patients are optimally treated to ensure the improvement and/or maintenance of their vision while reducing unnecessary treatment burden.

According to another aspect of the present invention, methods, uses, bispecific antibodies (for use), drugs for treating patients suffering from specific neovascular AMD (nAMD) (also known as wet AMD (wAMD)) are provided Or a pharmaceutical formulation, the method comprising administering to the patient an effective amount of dual specificity combined with human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) in a personalized treatment interval (PTI) regimen Antibodies, wherein the treatment of patients suffering from nAMD includes prolonging the dosing interval in the case of stable absence of the disease or shortening the dosing schedule of the interval in the presence of disease activity. In this way, patients are optimally treated to ensure the improvement and/or maintenance of their vision while reducing unnecessary treatment burden.

According to one aspect of the present invention, there are provided methods, uses, bispecific antibodies (for use), drugs or pharmaceutical formulations for treating afflicted patients, the method comprising administering to the patient an effective amount of binding to human vascular endothelium Bispecific antibody of growth factor (VEGF) and human angiopoietin-2 (ANG-2), Among them, the treatment of patients suffering from AMD includes prolonging the dosing interval in the case of stable absence of the disease after the start of the treatment or shortening the dosing schedule in the case of disease activity.

One embodiment is such a method, use, bispecific antibody (for use), drug or pharmaceutical formulation for the treatment of patients suffering from neovascular AMD (nAMD), the method comprising administering to the patient at a personalized treatment interval An effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), wherein a) The patient is first treated with the bispecific VEGF/ANG2 antibody for 4 times at a dosing interval every 4 weeks (Q4W); b) Assessment of disease activity at the 20th and 24th week, in which the determination of whether the disease activity meets one of the following criteria: i) Compared with the average CST value of the two previous scheduled visits, the central subfield thickness (CST) of the macula has increased> 50 μm. The 20th week assessment is based on the 12th and 16th week visits and The 24th week assessment is for the 16th and 20th visits, or ii) Compared with the lowest CST value recorded during any of the two previous scheduled visits, the CST increased by ≥ 75 μm; iii) Due to nAMD disease activity, BCVA decreased by ≥ 5 letters compared with the average best corrected visual acuity (BCVA) value of the two previous scheduled visits, iv) Due to nAMD disease activity, the BCVA decreased by ≥ 10 letters compared to the highest BCVA value recorded during any of the previous two scheduled visits, or v) New macular hemorrhage due to nAMD activity c) Follow the patient i) Patients who meet the criteria for disease activity in the 20th week will be treated at an 8-week (Q8W) dosing interval starting from the 20th week (the first Q8W dose will be given at the 20th week); ii) Patients who meet the criteria for disease activity in the 24th week will be treated at 12-week (Q12W) dosing intervals starting from the 24th week (the first Q12W dosing will be given in the 24th week); and iii) Patients who do not meet the criteria for disease activity in the 20th and 24th weeks will be treated at a 16-week (Q16W) dosing interval starting from the 28th week (the first Q16W dose is given at the 28th week) .

In one embodiment, after the 60th week, the personalized treatment interval will be extended, shortened, or maintained, where a) When all the following criteria are met, the interval is extended by 4 weeks (to the maximum Q16W): i) Compared with the average value of the last two study drug administration visits, CST is stable. Stability is defined as the change of CST less than 30 µm and compared with the lowest measured value of the drug administration visit in the study, CST No increase ≥ 50 µm, ii) Compared with the average of the last two study drug administration visits, BCVA did not decrease by ≥ 5 letters, and compared with the highest study drug administration visit measurement value, BCVA did not decrease by ≥ 10 letters , iii) No new macular hemorrhage; b) The interval shall be shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or In the event that two or more of the following criteria are met or one criterion includes new macular hemorrhage, shorten the interval to 8 weeks: i) Compared with the average of the last two dosing visits, the CST increased by ≥ 50 µm, or compared with the lowest dosing visit measurement value, the CST increased by ≥ 75 µm, ii) Compared with the average of the last two dosing visits, the BCVA decrease is ≥ 5 letters, or compared with the highest dosing visit measurement value, the BCVA decreases ≥ 10 letters, iii) New macular hemorrhage.

According to another aspect of the present invention, there are provided methods, uses, bispecific antibodies (for use), drugs or pharmaceutical formulations for treating patients suffering from diabetic retinopathy, specifically diabetic macular edema (DME) The method comprises administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) in a personalized treatment interval (PTI) regimen, which suffers from Treatment of patients with DME includes extending the dosing interval in the presence of stable disease-free conditions or shortening the dosing schedule in the presence of disease activity. In this way, patients are optimally treated to ensure the improvement and/or maintenance of their vision while reducing unnecessary treatment burden.

One embodiment is such a method, use, bispecific antibody (for use), drug or pharmaceutical formulation for the treatment of a patient suffering from diabetic macular edema (DME), the method comprising administering to the patient at a personalized treatment interval An effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), wherein a) The patient is first treated with the bispecific VEGF/ANG2 antibody at a dosing interval of 4 weeks (Q4W) until the central retinal thickness (CST) of the macula meets the predetermined reference CST threshold (for the Spectralis spectrum macular center Retina thickness SD-OCT, CST <325 µm, or for Cirrus SD-OCT or Topcon SD-OCT, CST <315 µm) (as measured on or after the 12th week); b) The subsequent dosing interval is increased by 4 weeks, to the initial dosing interval every 8 weeks (Q8W); c) From now on, extend, shorten or maintain the dosing interval based on the assessments performed during the dosing visits based on the CST and best corrected visual acuity (BCVA) and the respective reference CST and BCVA Relative change in comparison; among them i) In the following cases, the interval is extended by 4 weeks, -The CST value increased or decreased by ≤ 10%, and there is no related BCVA decrease by ≥ 10 letters; ii) Maintain this interval in the following cases: -The CST reduction> 10%, or -The CST value increased or decreased by ≤ 10%, and the associated BCVA decreased by ≥ 10 letters, or -The CST value increased> 10% and ≤ 20%, and there is no related BCVA decrease ≥ 5 letters; iii) In the following cases, the interval is shortened by 4 weeks -The CST value increased by> 10% and ≤ 20%, with the associated decrease in BCVA by ≥ 5 to <10 letters; or -The CST value increased by ＞ 20%, and there is no related BCVA decrease by ≥ 10 letters; iv) In the case where the CST value increases> 10%, and the related BCVA decreases ≥ 10 letters, the interval is shortened by 8 weeks; Among them, when the initial CST threshold is met, the respective reference macular central retinal thickness (CST) is the CST value, and the CST is reduced by> 10% compared to the previous reference CST of two consecutive dosing visits Adjust the reference CST, and the obtained values are within 30 µm, so that the CST value obtained during subsequent visits will serve as the new reference CST; and The reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any previous dosing visit.

In one embodiment, such dosing intervals can be adjusted in 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

According to another aspect of the present invention, methods, uses, and bispecific antibodies for the treatment of patients suffering from macular edema secondary to central retinal vein occlusion, semi-retinal vein occlusion or branch vein occlusion are provided (For use), a drug or a pharmaceutical formulation, the method comprises administering to the patient an effective amount of human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG- 2) The bispecific antibody, in which the treatment of patients suffering from macular edema secondary to central retinal vein occlusion, semi-retinal vein occlusion or branch vein occlusion includes prolonged administration in the absence of stable disease Interval or shorten the interval dosing schedule in the presence of disease activity. In this way, patients are optimally treated to ensure the improvement and/or maintenance of their vision while reducing unnecessary treatment burden.

One embodiment is such methods, uses, bispecific antibodies (for use) for the treatment of patients suffering from macular edema secondary to central retinal vein occlusion, semi-retinal vein occlusion or secondary venous occlusion , A drug or a pharmaceutical formulation, the method comprising administering to the patient an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) at a personalized treatment interval, among them a) The patient is first treated with the bispecific VEGF/ANG2 antibody at a dosing interval of 4 weeks (Q4W) from day 1 to week 20; b) From the 24th week, the patient receives the bispecific VEGF/ANG2 antibody at the Q4W frequency until the central retinal thickness (CST) of the macula meets the predetermined reference CST threshold; c) From now on, extend, shorten or maintain the dosing interval based on the assessments performed during the dosing visits based on the CST and best corrected visual acuity (BCVA) and the respective reference CST and BCVA Relative change in comparison; among them i) In the following cases, the interval is extended by 4 weeks The CST value increased or decreased by ≤ 10% without a related BCVA decrease by ≥ 10 letters; or ii) Maintain this interval if any of the following criteria is met: The CST value is reduced by> 10%; or The CST value is reduced by ≤ 10%, with associated BCVA reduction by ≥ 10 letters, or The CST value increased by more than 10% and less than 20%, and there is no related BCVA decreased by more than 5 letters; iii) If any of the following criteria is met, the interval is shortened by 4 weeks: The CST value increased by> 10% and ≤ 20%, with associated BCVA decrease by ≥ 5 to <10 letters, or The CST value increased by> 20% without a related decrease in BCVA by ≥ 10 letters; or The CST value increased by ≤ 10%, and the associated BCVA decreased by ≥ 10 letters; iv) In the following cases, the interval is shortened to Q4W The CST value increased by> 10%, and the associated BCVA decreased by ≥ 10 letters, Among them, when the initial CST threshold is met, the respective reference macular central retinal thickness (CST) is the CST value, and the CST is reduced by> 10% compared to the previous reference CST of two consecutive dosing visits Adjust the reference CST, and the obtained values are within 30 µm, so that the CST value obtained during subsequent visits will serve as the new reference CST; and The reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any previous dosing visit.

In one embodiment, such dosing intervals can be adjusted in 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. In one embodiment of the present invention, the bispecific antibody that binds to human VEGF and human ANG2 is a bispecific bivalent anti-VEGF/ANG2 antibody, which includes a first antigen binding site that specifically binds to human VEGF and a specific Sexually binds to the second antigen binding site of human ANG-2, where i) The first antigen binding site that specifically binds to VEGF includes the CDR3H region of SEQ ID NO: 1, the CDR2H region of SEQ ID NO: 2, and the CDR1H region of SEQ ID NO: 3 in the heavy chain variable domain, And the light chain variable domain includes the CDR3L region of SEQ ID NO: 4, the CDR2L region of SEQ ID NO: 5, and the CDR1L region of SEQ ID NO: 6; and ii) The second antigen binding site that specifically binds to ANG-2 includes the CDR3H region of SEQ ID NO: 9, the CDR2H region of SEQ ID NO: 10, and the CDR1H of SEQ ID NO: 11 in the heavy chain variable domain Region, and includes the CDR3L region of SEQ ID NO: 12, the CDR2L region of SEQ ID NO: 13 and the CDR1L region of SEQ ID NO: 14 in the light chain variable domain, and wherein iii) The bispecific antibody contains the constant heavy chain region of the human IgG1 subclass, which contains the mutations I253A, H310A and H435A and the mutations L234A, L235A and P329G (numbered according to the EU index of Kabat).

In one embodiment of the present invention, patients suffering from ocular vascular disease have not previously been treated (as untreated) with anti-VEGF therapy (eg, monotherapy).

In one embodiment of the present invention, patients suffering from ocular vascular disease have previously been treated with anti-VEGF therapy (e.g., monotherapy).

In one embodiment of the present invention, the disclosed bispecific antibody is administered according to the measurement of a software tool.

The methods, uses, bispecific antibodies (for use), drugs or pharmaceutical formulations for the treatment of ocular vascular diseases selected from nAMD and DME include sequential administration of initial doses ("treatment initial"). In some embodiments, the initial dose may be changed from once every 3 months to once every 7 months; in one embodiment, the initial treatment includes once every 3 to 4 months, and in one embodiment, the initial treatment includes Dosing once every 4 to 5 months; in one embodiment, the initial treatment includes once every 4 to 6 months; in one embodiment, the initial treatment includes at least once every 4 months; in one embodiment, the initial treatment includes The drug is administered every 5 to 7 months. In one embodiment, the initial treatment includes administration every 6 months.

In one embodiment of the invention, the bispecific antibody, drug or pharmaceutical formulation (under each treatment) is administered in a dose of about 5 to 7 mg. In one example, the bispecific antibody (under each treatment) is administered at a dose of 6 mg +/- 10%. In one example, the bispecific antibody (under each treatment) is administered at a dose of about 6 mg (in one example, at a dose of 6 mg (under each treatment)).

In one embodiment of the invention, the bispecific antibody, drug or pharmaceutical formulation is administered at a bispecific antibody concentration of about 120 mg/ml (+/- 12 mg/ml).

Macular degeneration is a medical condition mainly found in elderly adults, in which the center of the lining of the eye, called the macular area of the retina, suffers from thinning, atrophy, and in some cases bleeding. This leads to loss of central vision, which causes the inability to see fine details, read or recognize faces. According to the American Academy of Ophthalmology, it is the main cause of central vision loss (blindness) over the age of fifty in the United States today. Although some macular dystrophy that affects younger individuals is sometimes referred to as macular degeneration, the term generally refers to age-related macular degeneration (AMD or ARMD).

As used herein, "age-related macular degeneration (AMD)" refers to a serious eye condition when the small central part of the retina called the macula deteriorates. AMD includes wet AMD and neovascular AMD. The wet form of AMD (wet AMD, wAMD or also known as neovascular AMD, nAMD) is characterized by abnormal blood vessels growing from the choroid below the macula. This is called choroidal neovascularization. These blood vessels leak blood and fluids (under and below the retina) into the retina, resulting in visual distortion (retina elevation and) that makes straight lines look wavy, as well as blind spots and loss of central vision. These abnormal blood vessels eventually become scarred, leading to permanent loss of central vision. Symptoms of AMD include darkness and blurring of the central area of vision; and decreased or altered color perception. AMD can be detected during routine eye examinations. One of the most common early signs of macular degeneration is drusen which is a tiny yellow deposit under the retina and pigment aggregation.

Advanced AMD, which causes profound vision loss, has two forms: dry and wet. Central geographic atrophy, that is, the dry form of advanced AMD is caused by atrophy of the retinal pigment epithelium layer below the retina, which causes vision loss through the loss of photoreceptors (rods and cones) in the central part of the eye. Although no treatment is available for this condition, vitamin supplements with high doses of antioxidants, lutein and zeaxanthin have been confirmed by the National Eye Institute and other institutions to slow the progression of dry macular degeneration and Improve vision in some patients.

As used herein, "diabetic macular edema" (DME) refers to a serious eye condition that affects people with diabetes (type 1 or type 2). Macular edema occurs when blood vessels in the retina leak into the macula and fluid and protein deposits collect on or below the macula of the eye and make it thick and swollen (edema). When the macula is near the center of the retina on the back of the eyeball, the swelling may distort a person's central vision. The main symptoms of DME include (but are not limited to) blurred vision, floating objects, loss of contrast, double vision, and final loss of vision. The pathology of DME is characterized by the breakdown of the blood-retinal barrier, which usually prevents fluid from moving in the retina, thus causing the fluid to accumulate in the retinal tissue and the retina is thickened. DME is currently diagnosed during an eye exam, which consists of a vision test (which measures the smallest letter that an individual can read on a standardized chart), dilated eye exams to check for signs of disease, and imaging tests (such as optical coherent tomography (OCT)). ) Or fluorescein angiography (FA) and pressure measurement), equipment (which measures the internal pressure of the eye). The following studies were also performed to determine treatment: optical coherent tomography (OCT), fluorescein angiography, and color stereo fundus photography. DME can be broadly characterized into two main categories: focal and diffuse. Focal DME is characterized by specific areas of individual and different leakage in the macula with sufficient macular blood flow. Diffuse DME is produced by the leakage of the entire capillary bed around the macula, which is produced by the breakdown of the blood-retinal barrier inside the eye. In addition to focal and diffuse, DME is also classified into clinically significant macular edema (CSME), non-CSME, and CSME with central participation (CSME-CI) based on clinical examination results, which involve the fovea. The present invention includes methods for the treatment of DME in the above-mentioned categories.

Retinal vein occlusion (RVO) is one of the most common retinal vascular disorders and is related to the degree of change in vision loss (Hayreh and Zimmerman 1994). After diabetic retinopathy (DR), RVO has been reported as the second leading cause of blindness in patients suffering from retinal vascular disease (Cugati S, Wang JJ, Rochtchina E et al., Arch Ophthalmol 2006; 124:726-732; Klein R, Knudtson MD, Lee KE et al., Ophthalmology 2008; 115: 1859-1868; Rogers S, McIntosh RL, Cheung N, et al., Ophthalmology February 2010; 117: 313-9.e1; Yasuda M, Kiyohara Y, Arakawa S Et al., Invest Ophtahlmol Vis Sci 2010;51:3205-3209).

The main types of RVO include branch retinal vein occlusion (BRVO), semi-retinal vein occlusion (HRVO) and central retinal vein occlusion (CRVO). The most common manifestation of RVO is the sudden and painless drop in central vision caused by macular edema.

The main types of macular edema secondary to RVO include macular edema secondary to branch retinal vein occlusion (BRVO), macular edema secondary to semiretinal vein occlusion (HRVO), and central retinal vein occlusion (CRVO). Macular edema.

At lower frequencies, patients may present with a history of instantaneous vision loss, lasting several seconds to several minutes, and complete restoration of vision. These symptoms may recur within a few days to a few weeks, followed by permanent loss of vision. Metamorphopsia and visual field defect have also been described (Achiron A, Lagstein O, Glick M, etc., Acta Ophthalmologica 2015; 93: e649-53; Manabe K, Osaka R, Nakano Y, etc. People, PLoS One 2017;12:e0186737).

The pathogenesis of macular edema in these patients begins with the increase in intraluminal pressure caused by blood vessel blockage, which causes the area of perfusion and ischemia to decrease. Ischemia causes upregulation and secretion of vascular endothelial growth factor (VEGF) (Boyd SR, Zachary I, Chakravarthy U et al., Arch Ophthalmol 2002; 12:1644-1650; Noma H, Minamoto A, Funatsu H et al., Graefes Arch Clin Exp Ophthalmol 2006;244:309-315) and Angiopoietin-2 (Ang-2), both of which are well-known pro-angiogenesis and vascular hyperpermeability cytokines, of which Ang-2 contributes to additional inflammation and Vascular instability (Maisonpierre PC, Suri C, Jones PF et al., Science 1997; 277:55-60; Hackett SF, Ozaki H, Strauss RW et al., J Cell Physiol 2000; 184:275-284; Fiedler U, Reiss Y, Scharpfenecker M et al., Nat Med 2006;12:235-239. Electronic version: February 5, 2006). Among all retinal vascular diseases, patients with RVO have been found to have the highest vitreous content of Ang-2 and VEGF (Aiello LP, Avery RL, Arrigg PG et al., N Engl J Med 1994;331:1480-1487; Regula JT, Lundh von Leithner P, Foxton R et al., EMBO Mol Med 2016;8:1265-1288). In many patients, increased levels of Ang-2 and VEGF in retinal tissues cause pathological changes in the retina and also cause macular edema accompanied by decreased vision. The hallmarks of RVO are the characteristic patterns of retinal hemorrhage, distortion and retinal vein expansion in the entire affected retinal area (one quadrant of BRVO, two quadrants of HRVO and the entire retina of CRVO). In more severe cases, patients may experience retinal ischemia and subsequent retinal neovascularization, hemorrhage, and anterior neovascularization, leading to reddening of the iris or neovascular glaucoma, and some patients may develop optic disc edema.

Although macular edema due to RVO and diabetic macular edema (DME) have different sources, they share a common pathophysiology. It is characterized by thickening of the macula and pathological increase of retinal vascular permeability due to fluid accumulation (caused by blood-retinal barrier breakdown), which can cause irreversible vision loss in two diseases.

Anti-VEGF drug therapy is currently the mainstay for the treatment of macular edema caused by RVO and its efficacy has been confirmed in several key randomized clinical studies. However, in some cases, macular lasers and intravitreal (IVT) steroids are also used-especially Steroid implants. Although anti-VEGF is the most effective treatment for macular edema caused by RVO, data from anti-VEGF clinical trials show that many patients have not achieved the best best corrected visual acuity (BCVA) and anatomical results, and many require frequent Long-term injections are used to maintain the growth achieved during the initial intensive treatment. In addition, real-world data analysis shows that due to the suboptimal injection frequency, many patients with RVO did not achieve the growth achieved in clinical trials (Vaz-Pereira, S, Marques IP, Matias J et al., Eur J Ophthalmol 2017;27:756-761; Wecker T, Ehlken C, Buhler A et al., Br J Ophthalmol 2017;101:353-359; Jumper JM, Dugel PU, Chen S et al., Clin Ophthalmol 2018;12:621- 629). Data show that many patients with macular edema due to BRVO and many patients with macular edema due to CRVO require close monitoring and longer treatment periods and require longer-lasting and effective treatment options (Bhisitkul RB, Campochiaro PA, Shapiro H et al., Ophthalmology 2013; 120: 1057-1063; Scott IU, Neal NL, Van Veldhuisen et al., JAMA Ophthalmol 2019; E1-E10).

Non-clinical studies have shown that Ang-2 and VEGF act synergistically to regulate vascular structure and increase the permeability of retinal endothelial cells in vitro. Compared with the molar equivalent of anti-VEGF (lambizumab) or anti-Ang-2 alone, the bispecific monoclonal antibody flucipilizumab inhibits both Ang-2 and VEGF in non-human primates. The laser-induced CNV model caused a greater reduction in the leakage and severity of choroidal neovascular (CNV) lesions. Early experiments using a mouse model of spontaneous CNV showed that in terms of vascular growth, leakage, edema, leukocyte infiltration, and loss of light-receiving organs, the dual inhibition of Ang-2 and VEGF always outperformed any single target alone. Drug therapy inhibition (Regula JT, Lundh von Leithner P, Foxton R, et al., EMBO Mol Med 2016; 8: 1265-1288).

In addition, it was shown that the aqueous and vitreous concentrations of both Ang-2 and VEGF are up-regulated in patients with neovascular age-related macular degeneration (nAMD), DR and RVO (Tong JP, Chan WM, Liu DT et al., Am J Ophthalmol 2006;141:456-462; Penn JS, Madan A, Caldwell RB et al., Prog Retin Eye Res 2008;27:331-371.; Kinnunen K, Puustjärvi T, Teräsvirta M et al., Br J Ophthalmol 2009 ;93:1109-1115;Tuuminen R, Loukovaara S. Eye (Lond) 2014;28:1095-1099;Regula JT, Lundh von Leithner P, Foxton R et al., EMBO Mol Med 2016;8:1265-1288;Ng DS, Yip YW, Bakthavatsalam M et al., Sci Rep 2017;7:45081). Therefore, compared with anti-VEGF therapy alone, the simultaneous neutralization of the two targets Ang-2 and VEGF can further standardize the pathological ocular vascular structure. The data from the complete Phase II study of DME and nAMD (see below) also supports the hypothesis that targeting Ang-2 in diseases that affect retinal vascular structure has the potential to extend efficacy durability beyond the potential of anti-VEGF therapy alone.

Has been in two phase I studies (BP28936 in nAMD and JP39844 in nAMD and DME) and three phase II studies (BP29647 [AVENUE] and CR39521 [STAIRWAY] for nAMD and BP30099 [BOULEVARD] for DME) In the study of fluxipilimab for the treatment of nAMD and DME. Four global phase III studies are in progress: GR40349 (YOSEMITE) and GR40398 (RHINE) of DME and GR40306 (TENAYA) and GR40844 (LUCERNE) of nAMD.

Based on the mechanism of action of fluxipilimab, data from non-clinical and clinical trials, and the pathophysiology of macular edema caused by RVO, it is hypothesized that fluxipilimab can cause pathology compared with anti-VEGF monotherapy Stabilize the ocular vascular structure and improve the visual and anatomical results of RVO.

Macular edema secondary to RVO/RVO is the highest among retinal vascular diseases (Aiello LP, Avery RL, Arrigg PG et al., N Engl J Med 1994; 331:1480-1487; Regula JT, Lundh von Leithner P, Foxton R et al., EMBO Mol Med 2016;8:1265-1288). The efficacy of Ang-2 and VEGF inhibition in non-clinical models of angiogenesis and inflammation (Regula JT, Lundh von Leithner P, Foxton R et al., EMBO Mol Med 2016; 8: 1265-1288) and from patients with nAMD and DME The data from the Phase I and Phase II flucipilimab studies of the patients provide evidence of the effectiveness of pathological pathways, which are caused by all three retinal vascular diseases nAMD, DME/DR, and macular edema due to RVO Shared (Phase I study: BP28936 in nAMD; Phase II study: AVENUE in nAMD, STAIRWAY in nAMD and BOULEVARD in DME).

Due to the similar pathophysiology between DME and macular edema due to RVO, data from the Phase II BOULEVARD study are reported here. Although the triggers of macular edema in diabetic and RVO patients are different, the downstream pathophysiology of hypoxia-driven macular edema and subsequent vision loss is similar and consists of the same pro-angiogenesis, pro-inflammatory, vascular instability and vascular permeability factors (Including Ang-2, VEGF and Interleukin-6 (IL-6)) driven. The BOULEVARD study provides basic evidence of the positive benefit-risk profile of 6-mg IVT fluxipilimab injection for patients with DME and supports the further evaluation of fluxipilimab in the Phase III DME study. The study met its primary efficacy endpoint, confirming the average change from baseline BCVA at week 24 in patients treated with 6 mg fluxipilizumab and not treated with anti-VEGF compared with 0.3 mg lambizumab The statistically significant improvement. Use a method adapted according to the 4-meter Early Treatment of Diabetic Retinopathy Study [ETDRS] protocol (using the Early Treatment of Diabetic Retinopathy Study (ETDRS) similar chart) and generate individual letter scores to determine the best corrected visual acuity (BCVA). In one embodiment, the determination of BCVA in such methods, uses, bispecific antibodies (for use), drugs or pharmaceutical formulations is based on the Early Treatment of Diabetic Retinopathy Study (ETDRS) protocol adaptive visual acuity chart, and Evaluation is performed at a starting distance of 4 meters.

Disease activity is, for example, through the reduction of BCVA/ETDR letter scores and/or through macular thickening (which involves the center of the macula as the central retinal thickness (CST) (also known as central retinal subfossa thickness) spectrum light Coordinate tomography (SD-OCT)) to determine. In a preferred embodiment, the central retinal thickness (CST) of the macula is measured using spectral domain optical coherence tomography (SD-OCT). In a preferred embodiment, CST is ^{measured by Spectralis TM} device by spectral domain optical coherence tomography (SD-OCT); in a preferred embodiment, CST is measured by Cirrus ^TM device by spectral domain optical coherence Tomography (SD-OCT) measurement; in one embodiment, CST is measured by Topcon ^TM device by spectral domain optical coherence tomography (SD-OCT); in one embodiment, CST is measured by Optovue ^TM device Measured by spectral domain optical coherent tomography (SD-OCT). As used herein, the term "patient suffering from" refers to a human who exhibits one or more symptoms or indications of the ocular vascular disease as described herein and/or has been diagnosed with the ocular vascular disease as described herein. The term "patient suffering from..." may also include, for example, prior to treatment, exhibiting (or exhibiting) such as, for example, retinal angiogenesis, neovascularization, blood vessel leakage, thickening of the retina in the center of the fovea, and accompanying adjacent retinas Hard yellow secretions in the center of the thickened fovea and thickening of the retina by at least 1 disc area (any part of which is within 1 disc diameter of the center of the fovea), blurred vision, floating objects, loss of contrast, diplopia And individuals with one or more indications of vascular eye disease that ultimately loses vision.

As used herein, the term "patient" "suffering" from ocular vascular disease (such as nAMD or DME) can include a subset of the population that is more susceptible to nAMD or DME or can display elevated levels of nAMD-related or DME-related biomarkers . For example, "patients suffering from DME" may include individuals who have suffered from diabetes for more than 10 years and have frequent high blood glucose levels or high fasting blood glucose levels. In certain embodiments, the term "patient suffering from DME" includes individuals who had or were diagnosed with diabetes before or at the time of administration of the bispecific anti-VEGF/ANG2 antibody. In certain embodiments, the term "patient suffering from nAMD" includes individuals who are over 50 years old before or at the time of anti-VEGF/ANG2 antibody administration. In some embodiments, the term "patient suffering from" includes individuals who are smokers or individuals who suffer from hypertension or high cholesterol.

As used herein, the term "suffering from" ocular vascular diseases, such as macular edema secondary to branch retinal vein occlusion (BRVO), macular edema secondary to semiretinal vein occlusion (HRVO), or central retinal vein occlusion The ``patients'' of macular edema (CRVO) may include macular edema secondary to branch retinal vein occlusion (BRVO), macular edema secondary to semiretinal vein occlusion (HRVO), or central retinal vein occlusion ( (CRVO) macular edema affects or can display elevated levels of RVO-related biomarkers in a subset of the population. For example, "patients suffering from RVO or macular edema secondary to RVO" may include individuals with increased levels of VEGF, ANG2, or IL-6. In some embodiments, the term "patient suffering from" includes individuals who are smokers or individuals who suffer from hypertension or high cholesterol. The present invention includes methods or bispecific antibodies (for use), drugs or pharmaceutical formulations for treating, preventing, or reducing the severity of ocular vascular diseases, ocular vascular diseases, and these methods include methods for treating ocular vascular diseases, preventing ocular vascular diseases or reducing the severity of ocular vascular diseases. The subject is administered a therapeutically effective amount of a bispecific anti-VEGF/ANG2 antibody (or a drug or pharmaceutical formulation containing the bispecific anti-VEGF/ANG2 antibody), wherein the bispecific is administered to the individual (intravitreal) in multiple doses Antibodies, drugs or pharmaceutical formulations containing such bispecific anti-VEGF/ANG2 antibodies, for example, as part of a specific therapeutic dosing regimen.

One embodiment of the present invention is the treatment method, use, bispecific antibody (for use), drug or pharmaceutical formulation as described herein, wherein patients suffering from ocular vascular disease have not previously been treated with anti-VEGF treatment (e.g., single Medication) for treatment (untreated).

One embodiment of the present invention is the treatment method, use, bispecific antibody (for use), drug or pharmaceutical formulation as described herein, wherein patients suffering from ocular vascular disease have previously been treated with anti-VEGF (e.g., Monotherapy, such as treatment with lambizumab, aflibercept or brolocizumab).

An embodiment of the present invention is a method, a use, a bispecific antibody (for use), a drug or a pharmaceutical formulation for treating a patient suffering from neovascular AMD (nAMD), the method comprising giving the patient a personalized treatment interval Administer an effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), wherein a) The patient is first treated with the bispecific VEGF/ANG2 antibody for 4 times at a dosing interval every 4 weeks (Q4W); b) Assessment of disease activity at the 20th and 24th week, in which the determination of whether the disease activity meets one of the following criteria: i) Compared with the average CST value of the two previous scheduled visits, the central retinal thickness (CST) of the macula has increased> 50 μm. The 20th week assessment is for the 12th and 16th week visits and the 24th week assessment system For visits in weeks 16 and 20, or ii) Compared with the lowest CST value recorded during any of the two previous scheduled visits, the CST increased by ≥ 75 μm; iii) Due to nAMD disease activity, BCVA decreased by ≥ 5 letters compared with the average best corrected visual acuity (BCVA) value of the two previous scheduled visits, iv) Due to nAMD disease activity, the BCVA decreased by ≥ 10 letters compared to the highest BCVA value recorded during any of the previous two scheduled visits, or v) New macular hemorrhage due to nAMD activity c) Follow the patient i) Patients who meet the criteria for disease activity in the 20th week will be treated with Q8W dosing intervals from the 20th week (the first Q8W dosing will be given at the 20th week); ii) Patients who meet the criteria for disease activity at week 24 will be treated with Q12W dosing intervals from week 24 (where the first Q12W dosing will be given at week 24); and iii) Patients who do not meet the criteria for disease activity in the 20th and 24th weeks will be treated at the Q16W dosing interval from the 28th week (the first Q16W dosing will be given at the 28th week).

In one embodiment, after the 60th week, the personalized treatment interval will be extended, shortened, or maintained, where a) When all the following criteria are met, the interval is extended by 4 weeks (to the maximum Q16W): i) Compared with the average value of the last two study drug administration visits, CST is stable. Stability is defined as the change of CST less than 30 µm and compared with the lowest measured value of the drug administration visit in the study, CST No increase ≥ 50 µm, ii) Compared with the average of the last two study drug administration visits, BCVA did not decrease by ≥ 5 letters, and compared with the highest study drug administration visit measurement value, BCVA did not decrease by ≥ 10 letters , iii) No new macular hemorrhage; b) the interval In the case of meeting one of the following criteria, shorten 4 weeks (to a minimum of Q8W), or In the event that two or more of the following criteria are met or one criterion includes new macular hemorrhage, shorten the interval to 8 weeks: i) Compared with the average of the two most recent dosing visits, the CST increased by ≥ 50 µm, or compared with the lowest dosing visit measurement value, the CST increased by ≥ 75 µm, ii) Compared with the average of the last two dosing visits, the BCVA decreased by ≥ 5 letters, or compared with the highest dosing visit measurement value, the BCVA decreased by ≥ 10 letters, iii) New macular hemorrhage.

In one embodiment, the disease activity assessment before the personalized treatment interval will be visited at the 16th week and the 20th week, or at the 24th week and the 28th week.

In one embodiment, depending on the activity of the disease, the personalized treatment interval to be further extended, shortened, or maintained will be at different time points, such as between the 50th week and the 70th week, such as after the 52nd week or Start after the 65th week. Another embodiment of the present invention is a method, use, bispecific antibody (for use), drug or pharmaceutical formulation for the treatment of patients suffering from diabetic macular edema (DME), the method comprising a personalized treatment interval An effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is administered to the patient, wherein a) The patient is first treated with the bispecific VEGF/ANG2 antibody at a dosing interval of 4 weeks (Q4W) until the central retinal thickness (CST) of the macula meets the predetermined reference CST threshold (for the Spectralis spectrum macular center Retina thickness SD-OCT, CST <325 µm, or for Cirrus SD-OCT or Topcon SD-OCT, CST <315 µm) (as measured on or after the 12th week); b) The dosing interval is then increased by 4 weeks to the initial Q8W dosing interval; c) From now on, extend, shorten or maintain the dosing interval based on the assessments performed during the dosing visits based on the CST and best corrected visual acuity (BCVA) and the respective reference CST and BCVA Relative change in comparison; among them i) In the following cases, the interval is extended by 4 weeks, -The CST value increased or decreased by ≤ 10%, and there is no related BCVA decrease by ≥ 10 letters; ii) Maintain this interval in the following cases: -The CST reduction> 10%, or -The CST value increased or decreased by ≤ 10%, and the associated BCVA decreased by ≥ 10 letters, or -The CST value increased> 10% and ≤ 20%, and there is no related BCVA decrease ≥ 5 letters; iii) In the following cases, the interval is shortened by 4 weeks -The CST value increased by> 10% and ≤ 20%, with the associated decrease in BCVA by ≥ 5 to <10 letters; or -The CST value increased by ＞ 20%, and there is no related BCVA decrease by ≥ 10 letters; iv) In the case where the CST value increases> 10%, and the related BCVA decreases ≥ 10 letters, the interval is shortened by 8 weeks; Among them, when the initial CST threshold is met, the respective reference macular central retinal thickness (CST) is the CST value, and the CST is reduced by> 10% compared to the previous reference CST of two consecutive dosing visits Adjust the reference CST, and the obtained values are within 30 µm, so that the CST value obtained during subsequent visits will serve as the new reference CST; and The reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any previous dosing visit.

In one embodiment, such dosing intervals can be adjusted in 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W.

Another embodiment of the present invention is a method for treating patients or patients suffering from ocular vascular diseases selected from the group consisting of secondary central retinal vein occlusion, secondary semiretinal vein occlusion, or macular edema secondary to branch vein occlusion. Methods, uses, bispecific antibodies (for use), drugs or medicines for patients with ocular vascular diseases secondary to central retinal vein occlusion, semi-retinal vein occlusion, or macular edema secondary to branch vein occlusion A formulation, wherein the treatment includes a personalized treatment interval (PTI), wherein a) The patient is first treated with the bispecific VEGF/ANG2 antibody at a dosing interval of 4 weeks (Q4W) from day 1 to week 20; b) From the 24th week, the patient receives the bispecific VEGF/ANG2 antibody at the Q4W frequency until the central macular retinal thickness (CST) meets the predetermined reference CST threshold (for the Spectralis spectrum domain macular central retinal thickness SD-OCT , CST <325 µm, or for Cirrus SD-OCT or Topcon SD-OCT, CST <315 µm) (as measured on or after the 24th week); c) From now on, extend, shorten or maintain the dosing interval based on the assessments performed during the dosing visits based on the CST and best corrected visual acuity (BCVA) and the respective reference CST and BCVA Relative change in comparison; among them i) In the following cases, the interval is extended by 4 weeks The CST value increased or decreased by ≤ 10% without a related BCVA decrease by ≥ 10 letters; or ii) Maintain this interval if any of the following criteria is met: The CST value is reduced by> 10%; or The CST value is reduced by ≤ 10%, with associated BCVA reduction by ≥ 10 letters, or The CST value increased by more than 10% and less than 20%, and there is no related BCVA decreased by more than 5 letters; iii) If any of the following criteria is met, the interval is shortened by 4 weeks: The CST value increased by> 10% and ≤ 20%, with associated BCVA decrease by ≥ 5 to <10 letters, or The CST value increased by> 20% without a related decrease in BCVA by ≥ 10 letters; or The CST value increased by ≤ 10%, and the associated BCVA decreased by ≥ 10 letters; iv) In the following cases, the interval is shortened to Q4W The CST value increased by> 10%, and the associated BCVA decreased by ≥ 10 letters, Among them, when the initial CST threshold is met, the respective reference macular central retinal thickness (CST) is the CST value, and the CST is reduced by> 10% compared to the previous reference CST of two consecutive dosing visits Adjust the reference CST, and the obtained values are within 30 µm, so that the CST value obtained during subsequent visits will serve as the new reference CST; and The reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any previous dosing visit.

In one embodiment, such dosing intervals can be adjusted in 4-week increments to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. As used herein, "antibody" refers to a binding protein that contains an antigen binding site. As used herein, the term "binding site" or "antigen binding site" refers to one or more regions of the antibody molecule to which the ligand actually binds. The term "antigen binding site" includes antibody heavy chain variable domains (VH) and antibody light chain variable domains (VL) (VH/VL pair).

Antibody specificity refers to the selective recognition of a specific epitope of an antigen by an antibody. For example, natural antibodies are monospecific.

The "bispecific antibody" according to the present invention is an antibody with two different antigen binding specificities. The antibody of the present invention specifically targets two different antigens, with VEGF as the first antigen and ANG-2 as the second antigen.

As used herein, the term "monospecific" antibody refers to an antibody having one or more binding sites, each of which binds to the same epitope of the same antigen.

As used in this application, the term "valency" means that the antibody molecule has a specified number of binding sites. Therefore, the terms "bivalent", "tetravalent" and "hexavalent" respectively indicate that there are two binding sites, four binding sites, and six binding sites in an antibody molecule. The bispecific antibody according to the present invention is preferably "bivalent".

As used herein, the terms "bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2)", "bispecific anti-VEGF/ANG2 antibody" and "bispecific Sex <VEGF/ANG2> antibody" is interchangeable and refers to an antibody that has at least two different antigen binding sites, the first binding to VEGF and the second binding to ANG2.

Bispecific anti-VEGF/ANG2 antibodies are described, for example, in WO2010040508, WO2011/117329, WO2012/131078, WO2015/083978, WO2017/197199 and WO2014/009465. WO2014/009465 describes bispecific anti-VEGF/ANG2 antibodies specifically designed for the treatment of ocular vascular diseases. The bispecific anti-VEGF/ANG2 antibody of WO2014/009465 (the entire text of which is incorporated herein) is particularly suitable for the treatment and treatment scheduling of ocular vascular diseases as described herein.

In one embodiment, the bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is a bispecific anti-VEGF/ANG2 antibody that specifically binds to human The first antigen-binding site of VEGF and the second antigen-binding site that specifically bind to human ANG-2, wherein i) The first antigen binding site that specifically binds to VEGF includes the CDR3H region of SEQ ID NO: 1, the CDR2H region of SEQ ID NO: 2, and the CDR1H region of SEQ ID NO: 3 in the heavy chain variable domain, And the light chain variable domain includes the CDR3L region of SEQ ID NO: 4, the CDR2L region of SEQ ID NO: 5, and the CDR1L region of SEQ ID NO: 6; and ii) The second antigen binding site that specifically binds to ANG-2 includes the CDR3H region of SEQ ID NO: 9, the CDR2H region of SEQ ID NO: 10, and the CDR1H of SEQ ID NO: 11 in the heavy chain variable domain Region, and includes the CDR3L region of SEQ ID NO: 12, the CDR2L region of SEQ ID NO: 13 and the CDR1L region of SEQ ID NO: 14 in the light chain variable domain, and wherein iii) The bispecific antibody contains the constant heavy chain region of the human IgG1 subclass, which contains the mutations I253A, H310A and H435A and the mutations L234A, L235A and P329G (numbered according to the EU index of Kabat).

In one embodiment, such bispecific anti-VEGF/ANG2 antibodies are bivalent.

In one embodiment, such bispecific anti-VEGF/ANG2 antibodies are characterized by i) The first antigen binding site that specifically binds to VEGF includes the amino acid sequence of SEQ ID NO: 7 as the heavy chain variable domain VH, and includes the amino acid sequence of SEQ ID NO: 8 as the light chain Variable domain VL, and ii) The second antigen binding site that specifically binds to ANG-2 includes the amino acid sequence of SEQ ID NO: 15 as the heavy chain variable domain VH, and includes the amino acid sequence of SEQ ID NO: 16 as the light Chain variable domain VL.

In one aspect of the invention, such bispecific bivalent antibodies according to the invention are characterized by comprising a) The heavy and light chains of the first full-length antibody that specifically binds to VEGF; b) The modified heavy chain and modified light chain of the second full-length antibody that specifically binds to ANG-2, wherein the constant domains CL and CH1 replace each other.

This bispecific bivalent antibody type that specifically binds to the bispecific antibody of human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is described in WO 2009/080253 (including the club- Hole (Knobs-into-Hole modified CH3 domain). The antibody based on this bispecific bivalent antibody type was named CrossMAb.

In one embodiment, such bispecific bivalent anti-VEGF/ANG2 antibodies are characterized by comprising a) The amino acid sequence of SEQ ID NO: 17 is used as the heavy chain of the first full-length antibody, and the amino acid sequence of SEQ ID NO: 18 is used as the light chain of the first full-length antibody, and b) The amino acid sequence of SEQ ID NO: 19 is used as the modified heavy chain of the second full-length antibody, and the amino acid sequence of SEQ ID NO: 20 is used as the modified light chain of the second full-length antibody.

In one embodiment, such bispecific bivalent anti-VEGF/ANG2 antibody is characterized by comprising the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 . In a preferred embodiment, the bispecific bivalent anti-VEGF/ANG2 antibody is flucipilimab.

Therefore, one embodiment of the present invention is a bispecific bivalent antibody, which comprises a first antigen binding site that specifically binds to human VEGF and a second antigen binding site that specifically binds to human ANG-2, which is characterized by It includes the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20. In a preferred embodiment, the bispecific bivalent anti-VEGF/ANG2 antibody is flucipilimab.

In one embodiment, the CH3 domain of the bispecific bivalent antibody according to the present invention is changed by the "knob-and-hole" technique, which is described in detail in, for example, WO 96/027011, Ridgway JB et al. Protein Eng 9 (1996) 617-621; and Merchant, AM et al., Nat Biotechnol 16 (1998) 677-681. In this method, the interaction surface of the two CH3 domains is changed to increase the heterodimerization of the two heavy chains containing the two CH3 domains. Each of the two CH3 domains (of the two heavy chains) can be a "punch" and the other can be a "mortar". The introduction of a disulfide bridge stabilizes the heterodimer (Merchant, AM et al., Nature Biotech 16 (1998) 677-681; Atwell, S. et al. J. Mol. Biol. 270 (1997) 26-35) and increase output.

In a preferred aspect of the present invention, the bispecific anti-VEGF/ANG2 antibody according to the present invention is characterized by The CH3 domain of one heavy chain and the CH3 domain of the other heavy chain each meet at the interface, which contains the original interface between the antibody CH3 domains, Wherein the interface is changed to promote the formation of bispecific antibodies, where the change is characterized by: a) Change the CH3 domain of a heavy chain, In the original interface, the CH3 domain of one heavy chain meets the initial interface of the CH3 domain of the other heavy chain in the bispecific antibody, The amino acid residue is replaced by an amino acid residue with a larger side chain volume, thereby generating protrusions in the interface of the CH3 domain of one heavy chain, and the protrusions can be located in the void in the interface of the CH3 domain of the other heavy chain. Cavity And b) Change the CH3 domain of the other heavy chain, So that the original interface of the first CH3 domain in the bispecific antibody is encountered in the original interface of the second CH3 domain The amino acid residue is replaced with an amino acid residue having a smaller side chain volume, thereby creating a cavity in the interface of the second CH3 domain, and protrusions in the interface of the first CH3 domain can be positioned in the cavity.

Therefore, the bispecific anti-VEGF/ANG2 antibody used as described herein is preferably characterized by a) the CH3 domain of the heavy chain of the full-length antibody and b) the CH3 domain of the heavy chain of the full-length antibody each meet at an interface that includes the change in the original interface between the antibody CH3 domains; Where i) in the CH3 domain of a heavy chain The amino acid residue is replaced by an amino acid residue with a larger side chain volume, thereby generating protrusions in the interface of the CH3 domain of one heavy chain, and the protrusions can be located in the void in the interface of the CH3 domain of the other heavy chain. Cavity And where ii) In the CH3 domain of another heavy chain The amino acid residue is replaced with an amino acid residue having a smaller side chain volume, thereby creating a cavity in the interface of the second CH3 domain, and protrusions in the interface of the first CH3 domain can be positioned in the cavity.

Preferably, the amino acid residue with larger side chain volume is selected from the group consisting of arginine (R), phenylalanine (F), tyrosine (Y), tryptophan (W ).

Preferably, the amino acid residue with a smaller side chain volume is selected from the group consisting of alanine (A), serine (S), threonine (T), valine (V ).

In one aspect of the present invention, the two CH3 domains are further changed by introducing cysteine (C) as an amino acid in the corresponding position of each CH3 domain, so that two CH3 domains can be formed between the two CH3 domains. Sulfur bridge bond.

In one embodiment, the bispecific antibody contains T366W mutations in the CH3 domain of the "knob chain" and T366S, L368A, and Y407V mutations in the CH3 domain of the "hole chain". It is also possible to use additional interchain disulfide bridges between CH3 domains, for example, by introducing the S354C mutation into one CH3 domain and the Y349C mutation into another CH3 domain (Merchant, AM et al., Nature Biotech 16 ( 1998) 677-681).

In another preferred embodiment, the bispecific antibody contains the S354C and T366W mutations in one of the two CH3 domains and the Y349C, T366S, L368A, and Y407V mutations in the other of the two CH3 domains. In another preferred embodiment, the bispecific antibody contains Y349C, T366W mutations in one of the two CH3 domains and S354C, T366S, L368A, Y407V mutations in the other of the two CH3 domains ( An additional Y349C or S354C mutation in one CH3 domain and an additional S354C or Y349C mutation in another CH3 domain to form an interchain disulfide bridge) (Always numbered according to the EU index of Kabat (Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991)).

Other techniques for CH3 modification for enhancing heterodimerization are covered as alternatives of the present invention and are described in, for example, WO 96/27011, WO 98/050431, EP 1870459, WO 2007/110205, WO 2007/147901, WO 2009 /089004, WO 2010/129304, WO 2011/90754, WO 2011/143545, WO 2012/058768, WO 2013/157954 and WO 2013/096291.

In one embodiment, the heterodimerization method described in EP 1 870 459A1 is used instead. This method is based on introducing substitutions/mutations of oppositely charged charged amino acids at specific amino acid positions in the CH3/CH3 domain interface between the two heavy chains. A preferred embodiment of the multispecific antibody is the amino acid R409D and K370E mutations in the CH3 domain of one heavy chain of the multispecific antibody and the amino acid D399K and E357K mutations in the CH3 domain of the other heavy chain (according to Kabat EU index number).

In another embodiment, the multispecific antibody includes the amino acid T366W mutation in the CH3 domain of the "knob chain" and the amino acid T366S, L368A, and Y407V mutations in the CH3 domain of the "hole chain"; and additionally includes The amino acids R409D and K370E mutations in the CH3 domain of the "knob chain" and the amino acids D399K and E357K mutations in the CH3 domain of the "hole chain".

In one embodiment, the heterodimerization method described in WO2013/157953 is used instead. In one embodiment, the CH3 domain of one heavy chain contains the amino acid T366K mutation, and the CH3 domain of the other heavy chain contains the amino acid L351D mutation. In another embodiment, the CH3 domain of a heavy chain further contains an amino acid L351K mutation. In another embodiment, the CH3 domain of the other heavy chain further comprises an amino acid mutation selected from Y349E, Y349D, and L368E (in one embodiment, L368E).

In one embodiment, the heterodimerization method described in WO2012/058768 is used instead. In one embodiment, the CH3 domain of one heavy chain contains amino acid L351Y and Y407A mutations, and the CH3 domain of the other heavy chain contains amino acid T366A and K409F mutations. In another embodiment, the CH3 domain of the other heavy chain further comprises an amino acid mutation at positions T411, D399, S400, F405, N390, or K392. In one embodiment, the amino acid mutation is selected from the group consisting of: a) T411N, T411R, T411Q, T411K, T411D, T411E and T411W, b) D399R, D399W, D399Y and D399K, c) S400E, S400D, S400R and S400K, d) F405I, F405M, F405T, F405S, F405V and F405W, e) N390R, N390K and N390D, f) K392V, K392M, K392R, K392L, K392F and K392E.

In another embodiment, the CH3 domain of one heavy chain contains amino acid L351Y and Y407A mutations, and the CH3 domain of the other heavy chain contains amino acid T366V and K409F mutations. In another embodiment, the CH3 domain of one heavy chain contains the amino acid Y407A mutation, and the CH3 domain of the other heavy chain contains the amino acid T366A and K409F mutations. In another embodiment, the CH3 domain of the other heavy chain further includes amino acid K392E, T411E, D399R and S400R mutations.

In one embodiment, the heterodimerization method described in WO2011/143545 is used instead. In one embodiment, the amino acid modification according to WO2011/143545 is introduced into the CH3 domain of the heavy chain at a position selected from the group consisting of 368 and 409.

In one embodiment, the heterodimerization method described in WO2011/090762 is used instead, which also uses the above-mentioned pestle-and-mortar technique. In one embodiment, the CH3 domain of one heavy chain contains the amino acid T366W mutation, and the CH3 domain of the other heavy chain contains the amino acid Y407A mutation. In one embodiment, the CH3 domain of one heavy chain contains the amino acid T366Y mutation, and the CH3 domain of the other heavy chain contains the amino acid Y407T mutation.

In one embodiment, the multispecific antibody is of the IgG2 isotype, and the heterodimerization method described in WO2010/129304 is used instead.

In one embodiment, the heterodimerization method described in WO2009/089004 is used instead. In one embodiment, the CH3 domain of a heavy chain contains an amino acid substitution of K392 or N392 with a negatively charged amino acid (in one embodiment, glutamic acid (E) or aspartic acid (D); In another embodiment, it is K392D or N392D mutation), and the CH3 domain of the other heavy chain contains the amino acid substitution of D399, E356, D356 or E357 with positively charged amino acid (in one embodiment, lysine Acid (K) or arginine (R), in another embodiment D399K, E356K, D356K, or E357K substitution; and in even another embodiment, D399K or E356K mutation). In another embodiment, the CH3 domain of a heavy chain further comprises an amino acid substitution of K409 or R409 with a negatively charged amino acid (in one embodiment, glutamic acid (E) or aspartic acid (D) ); in another embodiment, K409D or R409D mutation). In another embodiment, the CH3 domain of a heavy chain further or alternatively includes substitution with negatively charged amino acids of K439 and/or K370 amino acids (in one embodiment, glutamine (E) or Aspartic acid (D)).

In one embodiment, the heterodimerization method described in WO2007/147901 is used instead. In one embodiment, the CH3 domain of one heavy chain includes amino acid K253E, D282K, and K322D mutations, and the CH3 domain of the other heavy chain includes amino acid D239K, E240K, and K292D mutations.

In one embodiment, the heterodimerization method described in WO2007/110205 is used instead.

In one embodiment, the bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is a bispecific anti-VEGF/ANG2 antibody that specifically binds to human The first antigen-binding site of VEGF and the second antigen-binding site that specifically bind to human ANG-2, wherein i) The first antigen binding site that specifically binds to VEGF includes the CDR3H region of SEQ ID NO: 1, the CDR2H region of SEQ ID NO: 2, and the CDR1H region of SEQ ID NO: 3 in the heavy chain variable domain, And the light chain variable domain includes the CDR3L region of SEQ ID NO: 4, the CDR2L region of SEQ ID NO: 5, and the CDR1L region of SEQ ID NO: 6; and ii) The second antigen binding site that specifically binds to ANG-2 includes the CDR3H region of SEQ ID NO: 9, the CDR2H region of SEQ ID NO: 10, and the CDR1H of SEQ ID NO: 11 in the heavy chain variable domain Region, and includes the CDR3L region of SEQ ID NO: 12, the CDR2L region of SEQ ID NO: 13 and the CDR1L region of SEQ ID NO: 14 in the light chain variable domain, and wherein iii) The bispecific antibody comprises the constant heavy chain region of the human IgG1 subclass, which contains the mutations I253A, H310A and H435A and the mutations L234A, L235A and P329G (numbered according to the EU index of Kabat); and wherein iv) In the constant heavy chain region, the T366W mutation is contained in one CH3 domain, and the T366S, L368A, and Y407V mutations are contained in another CH3 domain (numbering according to the EU index of Kabat).

In one embodiment, the bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is a bispecific anti-VEGF/ANG2 antibody that specifically binds to human The first antigen-binding site of VEGF and the second antigen-binding site that specifically bind to human ANG-2, wherein i) The first antigen binding site that specifically binds to VEGF includes the CDR3H region of SEQ ID NO: 1, the CDR2H region of SEQ ID NO: 2, and the CDR1H region of SEQ ID NO: 3 in the heavy chain variable domain, And the light chain variable domain includes the CDR3L region of SEQ ID NO: 4, the CDR2L region of SEQ ID NO: 5, and the CDR1L region of SEQ ID NO: 6; and ii) The second antigen binding site that specifically binds to ANG-2 includes the CDR3H region of SEQ ID NO: 9, the CDR2H region of SEQ ID NO: 10, and the CDR1H of SEQ ID NO: 11 in the heavy chain variable domain Region, and includes the CDR3L region of SEQ ID NO: 12, the CDR2L region of SEQ ID NO: 13 and the CDR1L region of SEQ ID NO: 14 in the light chain variable domain, and wherein iii) The bispecific antibody comprises the constant heavy chain region of the human IgG1 subclass, which contains the mutations I253A, H310A and H435A and the mutations L234A, L235A and P329G (numbered according to the EU index of Kabat); and wherein iv) In the constant heavy chain region, the S354C and T366W mutations are contained in one CH3 domain, and the Y349C, T366S, L368A and Y407V mutations are contained in the other CH3 domain (numbering according to Kabat's EU index).

In one embodiment, such bispecific anti-VEGF/ANG2 antibodies are bivalent.

In one embodiment, such bispecific anti-VEGF/ANG2 antibodies are characterized by i) The first antigen binding site that specifically binds to VEGF includes the amino acid sequence of SEQ ID NO: 7 as the heavy chain variable domain VH, and includes the amino acid sequence of SEQ ID NO: 8 as the light chain Variable domain VL, and ii) The second antigen binding site that specifically binds to ANG-2 includes the amino acid sequence of SEQ ID NO: 15 as the heavy chain variable domain VH, and includes the amino acid sequence of SEQ ID NO: 16 as the light Chain variable domain VL.

In one aspect of the invention, such bispecific bivalent antibodies according to the invention are characterized by comprising a) The heavy and light chains of the first full-length antibody that specifically binds to VEGF; b) The modified heavy chain and modified light chain of the second full-length antibody that specifically binds to ANG-2, wherein the constant domains CL and CH1 replace each other.

The term "VEGF" as used herein refers to human vascular endothelial growth factor (VEGF/VEGF-A), a 165 amino acid human vascular endothelial cell growth factor (human VEGF165 precursor sequence amino acid 27-191: SEQ ID NO: 24; amino acids 1-26 represent signal peptides), and related 121, 189 and 206 vascular endothelial cell growth factor isoforms, such as Leung, DW et al., Science 246 (1989) 1306-9 ; Houck et al., Mol. Endocrin. 5 (1991) 1806 -1814; Keck, PJ et al., Science 246 (1989) 1309-12 and Connolly, DT et al., J. Biol. Chem. 264 (1989) 20017- 24, as well as naturally occurring alleles and processed forms of these growth factors. VEGF is involved in the regulation of normal and abnormal angiogenesis and neovascularization associated with tumors and intraocular disorders (Ferrara, N. et al., Endocr. Rev. 18 (1997) 4-25; Berkman, RA et al., J. Clin) Invest. 91 (1993) 153-159; Brown, LF et al., Human Pathol. 26 (1995) 86-91; Brown, LF et al., Cancer Res. 53 (1993) 4727-4735; Mattern, J. et al. Human, Brit. J. Cancer. 73 (1996) 931-934; and Dvorak, HF et al., Am. J. Pathol. 146 (1995) 1029-1039). VEGF is a homodiglycan protein that has been separated from several sources and includes several isoforms. VEGF exhibits highly specific cell division activity of endothelial cells. VEGF antagonists/inhibitors inhibit the binding of VEGF to its receptor VEGFR. Known VEGF antagonists/inhibitors include bispecific anti-VEGF/ANG2 antibodies as described in WO2014/009465.

As used herein, the term "ANG-2" refers to human angiopoietin-2 (ANG-2) (alternatively abbreviated as ANGPT2 or ANG2) (SEQ ID NO: 25), which is described in, for example, Maisonpierre, PC et al. , Science 277 (1997) 55-60 and Cheung, AH et al., Genomics 48 (1998) 389-91. It was found that Angiopoietin-1 (SEQ ID NO: 26) and Angiopoietin-2 are ligands of Tie, which are the tyrosine kinase family that are selectively expressed in vascular endothelium (Yancopoulos, GD et al., Nature 407 (2000) 242-48). There are four definite members of the angiopoietin family. Angiopoietin-3 and Angiopoietin-4 (Ang-3 and Ang-4) can represent very different counterparts of the same locus in mice and humans (Kim, I. et al., FEBS Let, 443 (1999) ) 353-56; Kim, I. et al., J Biol Chem 274 (1999) 26523-28). In tissue culture experiments, ANG-1 and ANG-2 were initially identified as agonists and antagonists (see ANG-1: Davis, S. et al., Cell 87 (1996) 1161-69; and ANG-2: Maisonpierre, PC et al., Science 277 (1997) 55-60). All known angiogenins mainly bind to its receptor TIE2 (SEQ ID NO: 27), and both Ang-1 and Ang-2 bind to TIE2 with an affinity (Kd) of 3 nM (Maisonpierre, PC et al., Science 277 (1997) 55-60). ANG2 antagonists/inhibitors inhibit the binding of ANG2 to its receptor TIE2. Known ANG2 antagonists/inhibitors include bispecific anti-VEGF/ANG2 antibodies as described in WO2014/009465.

The antigen binding site of the bispecific antibody of the present invention contains six complementarity determining regions (CDR), which promote the affinity of the binding site to the antigen to varying degrees. There are three heavy chain variable domain CDRs (CDRH1, CDRH2, and CDRH3) and three light chain variable domain CDRs (CDRL1, CDRL2, and CDRL3). The extent of CDR and framework regions (FR) is determined by comparison with a compiled database of amino acid sequences, where these regions have been defined based on the variability between sequences.

The antibody of the present invention comprises human-derived immunoglobulin constant regions derived from one or more immunoglobulin classes, where such immunoglobulin classes include IgG, IgM, IgA, IgD, and IgE classes, and in the case of IgG and IgA The following includes its subclasses, especially IgG1 and IgG4.

As used herein, the term "monoclonal antibody" or "monoclonal antibody composition" refers to a preparation of antibody molecules of a single amino acid composition.

The term "chimeric antibody" refers to an antibody comprising a variable region (ie, a binding region) from one source or species and at least a part of a constant region derived from a different source or species, which is usually prepared by recombinant DNA technology. Chimeric antibodies containing murine variable regions and human constant regions are preferred. Other preferred forms of "chimeric antibodies" encompassed by the present invention are those in which the constant region has been modified or changed from the original antibody to produce the characteristics according to the present invention, especially with respect to C1q binding and/or Fc receptor (FcR) binding. And other chimeric antibodies. Such chimeric antibodies are also called "class-switched antibodies". A chimeric antibody is an expression product of an immunoglobulin gene including a DNA segment encoding the variable region of an immunoglobulin and a DNA segment encoding the constant region of an immunoglobulin. The methods used to generate chimeric antibodies involve conventional recombinant DNA and gene transfection techniques well known in the art. See, for example, Morrison, S.L. et al., Proc. Natl. Acad. Sci. USA 81 (1984) 6851-6855; US 5,202,238 and US 5,204,244.

The term "humanized antibody" refers to a CDR in which the framework or "complementarity determining region" (CDR) has been modified to include an immunoglobulin with a different specificity than the CDR of the parental immunoglobulin. In a preferred embodiment, murine CDRs are grafted into the framework regions of human antibodies to prepare "humanized antibodies". See, for example, Riechmann, L. et al., Nature 332 (1988) 323-327; and Neuberger, M.S. et al., Nature 314 (1985) 268-270. Particularly preferred CDRs correspond to those CDRs representing sequences that recognize the antigen mentioned above for the chimeric antibody. Other forms of "humanized antibodies" covered by the present invention are those in which the constant region has been additionally modified or changed from the original antibody to produce the properties according to the present invention (especially with respect to C1q binding and/or Fc receptor (FcR) binding). And other humanized antibodies.

As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Known in the art related to human antibodies (van Dijk, M.A. and van de Winkel, J.G., Curr. Opin. Chem. Biol. 5 (2001) 368-374). Human antibodies can also be produced in transgenic animals (e.g., mice), which can produce a complete lineage or selected human antibodies when immunized without producing endogenous immunoglobulins. The transfer of human germline immunoglobulin gene arrays to such germline mutant mice will be able to produce human antibodies when challenged by antigens (see, for example, Jakobovits, A. et al., Proc. Natl. Acad. Sci. USA 90 ( 1993) 2551-2555; Jakobovits, A. et al., Nature 362 (1993) 255-258; Brueggemann, M. et al., Year Immunol. 7 (1993) 33-40). Human antibodies can also be produced in phage display pools (Hoogenboom, HR and Winter, G., J. Mol. Biol. 227 (1992) 381-388; Marks, JD et al., J. Mol. Biol. 222 (1991) ) 581-597). The techniques of Cole, A. et al. and Boerner, P. et al. can also be used to prepare human monoclonal antibodies (Cole, A. et al., Monoclonal Antibodies and Cancer Therapy, Liss, AL, p. 77 (1985); and Boerner , P. et al., J. Immunol. 147 (1991) 86-95). As already mentioned for the chimeric and humanized antibodies according to the present invention, the term "human antibody" as used herein also encompasses modifications in the constant region to produce properties according to the present invention, especially with regard to C1q binding and/or FcR Such antibodies bind, for example, by "class switching", that is, changes or mutations in the Fc part (for example, mutations from IgG1 to IgG4 and/or IgG1/IgG4).

As used herein, the term "recombinant antibody" is intended to include all human antibodies prepared, expressed, formed or isolated by recombinant means, such as from host cells such as NS0 or CHO cells or from animals that have been transfected with human immunoglobulin genes ( For example, a mouse) isolated antibody, or an antibody expressed using a recombinant expression vector transfected into a host cell. Such recombinant antibodies have variable and constant regions in a rearranged form. The recombinant antibody according to the present invention has undergone somatic hypermutation in vivo. Therefore, the amino acid sequences of the VH region and VL region of the recombinant antibody are derived from the human germline VH sequence and VL sequence and are related to the human germline VH sequence and VL sequence, but are not necessarily naturally present in the living body. The sequence within the pedigree.

As used herein, "variable domain" (variable domain of light chain (VL), variable domain of heavy chain (VH)) means each of a pair of light chain and heavy chain, which directly relates to antibody and antigen Combine. The variable human light chain and heavy chain domains have the same general structure and each domain contains four framework (FR) regions, and their sequences are widely conserved. They are determined by three "hypervariable regions" (or complementarity determinations). Region, CDR) connection. The framework region adopts the β-sheet configuration and the CDR can form a loop connecting the β-sheet structure. The CDRs in each chain are maintained in their three-dimensional structure by the framework regions and form an antigen binding site together with the CDRs from the other chain. The antibody heavy chain and light chain CDR3 regions play a particularly important role in the binding specificity/affinity of the antibody according to the present invention and therefore provide another object of the present invention.

As used herein, the term "hypervariable region" or "antigen-binding portion of an antibody" refers to the amino acid residues of the antibody that are responsible for antigen binding. The hypervariable region contains amino acid residues from the "complementarity determining region" or "CDR". "Framework" or "FR" regions are those variable domain regions other than hypervariable region residues as defined herein. Therefore, the light chain and the heavy chain of an antibody include domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 from N-terminus to C-terminus. The CDRs on each chain are separated by such framework amino acids. In particular, CDR3 of the heavy chain is the most conducive region for antigen binding. The CDR and FR regions are determined according to the standard definitions of Kabat, E.A. et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991).

The term "full-length antibody" refers to an antibody composed of two "full-length antibody heavy chains" and two "full-length antibody light chains". "Full-length antibody heavy chain" is composed of antibody heavy chain variable domain (VH), antibody constant heavy chain domain 1 (CH1), antibody hinge region (HR), antibody heavy chain constant domain 2 ( CH2) and antibody heavy chain constant domain 3 (CH3) (abbreviated as VH-CH1-HR-CH2-CH3) and optional antibody heavy chain constant domain 4 (CH4) in the case of subclass IgE antibodies Peptides. Preferably, the "full-length antibody heavy chain" is a polypeptide composed of VH, CH1, HR, CH2, and CH3 in the N-terminal to C-terminal direction. A "full-length antibody light chain" is a polypeptide composed of an antibody light chain variable domain (VL) and an antibody light chain constant domain (CL) (abbreviated as VL-CL) in the N-terminal to C-terminal direction. The antibody light chain constant domain (CL) can be κ (kappa) or λ (lambda). The two full-length antibody chains are linked together via inter-polypeptide disulfide bonds between the CL domain and the CH1 domain and between the hinge region of the full-length antibody heavy chain. Examples of typical full-length antibodies are natural antibodies such as IgG (eg, IgG1 and IgG2), IgM, IgA, IgD, and IgE. The full-length antibody according to the present invention may be from a single species, such as human, or it may be a chimeric or humanized antibody. The full-length antibody according to the present invention contains two antigen binding sites each formed by a pair of VH and VL, both of which specifically bind to the same antigen. The C-terminus of the heavy or light chain of the full-length antibody represents the last amino acid at the C-terminus of the heavy or light chain. The N-terminus of the heavy or light chain of the full-length antibody represents the last amino acid at the N-terminus of the heavy or light chain.

The term "constant region" as used in this application refers to the sum of the domains of antibodies other than the variable region. The constant region is not directly involved in binding antigen, but exhibits various effector functions. Depending on the amino acid sequence of the constant region of the antibody heavy chain, antibodies are divided into the following categories: IgA, IgD, IgE, IgG, and IgM, and several of these categories can be further divided into subclasses, such as IgG1, IgG2, IgG3 and IgG4, IgA1 and IgA2. The heavy chain constant regions corresponding to different classes of antibodies are called α, δ, ε, γ, and μ, respectively. The light chain constant regions that can be found in all five antibody classes are called kappa (kappa) and lambda (lambda).

As used in this application, the term "constant region derived from human sources" or "human constant region" refers to the constant heavy chain region and/or constant light chain κ or λ of a human antibody of subclass IgG1, IgG2, IgG3 or IgG4 Area. Such constant regions are well known in the current advanced technology, and are described, for example, by Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991) ( See also, for example, Johnson, G. and Wu, TT, Nucleic Acids Res. 28 (2000) 214-218; Kabat, EA et al., Proc. Natl. Acad. Sci. USA 72 (1975) 2785-2788). In the application for the numbering of positions and mutations, use the EU numbering system according to Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991) (EU index) and called "EU index number according to Kabat".

In one embodiment, the bispecific antibody according to the invention has a constant region of the human IgG1 subclass (derived from the human IgG1 subclass). However, the C-terminal lysine (Lys447) or C-terminal glycine (Gly446) and C-terminal lysine (Lys447) of the Fc region may or may not be present.

In one embodiment, the bispecific antibody as described herein belongs to the IgG1 isotype/subclass and comprises the constant heavy chain domain of SEQ ID NO: 23 or the constant part of the heavy chain amino acid sequence of SEQ ID NO: 17 and The constant part of the heavy chain amino acid sequence of SEQ ID NO: 18. In one embodiment, C-terminal glycine (Gly446) is additionally present. In one embodiment, C-terminal glycine (Gly446) and C-terminal lysine (Lys447) are additionally present.

Unless otherwise specified herein, the numbering of amino acid residues in the constant region is based on the EU numbering system, which is also known as the EU index of Kabat, such as Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991), NIH Publication 91-3242.

In one embodiment, the bispecific antibody according to the present invention belongs to the human IgG1 subclass with mutations L234A (Leu235Ala), L235A (Leu234Ala) and P329G (Pro329Gly). Such antibodies have reduced FcR binding (in particular, they no longer display binding to FcRγI, FcRγII, and FcRγIII). This is particularly suitable for reducing potential side effects, such as thrombosis (Meyer, T. et al., J. Thromb. Haemost. 7 (2009) 171-81).

Although the described Pro329Ala mutation only removes two-thirds of the FcγRIIIa sandwich interaction, the Pro329Gly in the antibody according to the present invention fully confers the binding of the Fc portion to FcγRIII. This is particularly applicable because the binding to FcγIII involves ADCC (antibody-dependent cytotoxicity) that causes cell death, which can help treat cancer diseases, but it can cause serious side effects in antibody-based treatments of other vascular or immune diseases . Therefore, antibodies according to the present invention of the IgG1 subclass with the mutations L234A, L235A and P329G and the IgG4 subclass with the mutations S228P, L235E and P329G are particularly suitable because they no longer display binding to FcRγI, FcRγII and FcRγIII.

The "effective amount" of a medicament (for example, a pharmaceutical formulation or a bispecific anti-VEGF/ANG2 antibody) refers to an amount that is effective to achieve the desired therapeutic or prophylactic result in the necessary dose for a necessary period of time.

In one embodiment of the invention, the bispecific antibody, drug or pharmaceutical formulation as described herein is administered via intravitreal application, for example via intravitreal injection ("intravitreal" administration). This can be performed according to standard procedures known in the art. See, for example, Ritter et al., J. Clin. Invest. 116 (2006) 3266-76; Russelakis-Carneiro et al., Neuropathol. Appl. Neurobiol. 25 (1999) 196-206; and Wray et al., Arch. Neurol. 33 (1976) 183-5.

In some embodiments, the treatment kit of the present invention may contain one or more doses of the described bispecific antibody present in the drug or pharmaceutical formulation, suitable for intravitreal injection of the drug or pharmaceutical formulation The device and detailed instructions for the injection are suitable for the individual and the protocol. In these embodiments, the drug or pharmaceutical formulation is usually administered to the individual in need of treatment via intravitreal injection. This can be performed according to standard procedures known in the art. See, for example, Ritter et al., J. Clin. Invest. 116 (2006) 3266-76; Russelakis-Carneiro et al., Neuropathol. Appl. Neurobiol. 25 (1999) 196-206; and Wray et al., Arch. Neurol. 33 (1976) 183-5.

Regardless of the chosen route of administration, the bispecific antibody as described herein is formulated into a pharmaceutically acceptable dosage form by conventional methods known to those skilled in the art.

One embodiment is the therapeutic method or bispecific antibody (drug or pharmaceutical formulation) for the treatment of ocular vascular diseases as described in any one of the preceding claims, wherein the antibody is administered according to the measurement of a software tool.

Another embodiment is a method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for treating patients suffering from nAMD, the method comprising: Receive patient data in the computing system, the patient data includes CST and best corrected visual acuity (BCVA); and optionally information about the assessment of new macular hemorrhage; Use this calculation system to extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; and For different ocular vascular diseases, such as nAMD, DME, or macular edema secondary to RVO, PTI is obtained according to the dosing interval based on the guidelines as described herein.

Another embodiment is a computer device/computing system for use/implementation of this method. Description of amino acid sequence SEQ ID NO: 1 Heavy chain CDR3H, <VEGF> Lambizumab SEQ ID NO: 2 Heavy chain CDR2H, <VEGF> Lambizumab SEQ ID NO: 3 Heavy chain CDR1H, <VEGF> lambizumab SEQ ID NO: 4 Light chain CDR3L, <VEGF> lambizumab SEQ ID NO: 5 Light chain CDR2L, <VEGF> Lambizumab SEQ ID NO: 6 Light chain CDR1L, <VEGF> Lambizumab SEQ ID NO: 7 Heavy chain variable domain VH, <VEGF> Lambizumab SEQ ID NO: 8 Light chain variable domain VL, <VEGF> lambizumab SEQ ID NO: 9 Heavy chain CDR3H, <ANG-2> Ang2i_LC10 variant SEQ ID NO: 10 Heavy chain CDR2H, <ANG-2> Ang2i_LC10 variant SEQ ID NO: 11 Heavy chain CDR1H, <ANG-2> Ang2i_LC10 variant SEQ ID NO: 12 Light chain CDR3L, <ANG-2> Ang2i_LC10 variant SEQ ID NO: 13 Light chain CDR2L, <ANG-2> Ang2i_LC10 variant SEQ ID NO: 14 Light chain CDR1L, <ANG-2> Ang2i_LC10 variant SEQ ID NO: 15 Heavy chain variable domain VH, <ANG-2> Ang2i_LC10 variant SEQ ID NO: 16 Light chain variable domain VL, <ANG-2> Ang2i_LC10 variant SEQ ID NO: 17 Heavy chain 1 of <VEGF-ANG-2> CrossMAb IgG1 (VEGFang2-0016) with AAA mutation and P329G LALA mutation SEQ ID NO: 18 Heavy chain 2 of <VEGF-ANG-2> CrossMAb IgG1 (VEGFang2-0016) with AAA mutation and P329G LALA mutation SEQ ID NO: 19 Light chain 1 of <VEGF-ANG-2> CrossMAb IgG1 (VEGFang2-0016) with AAA mutation and P329G LALA mutation SEQ ID NO: 20 Light chain 2 of <VEGF-ANG-2> CrossMAb IgG1 (VEGFang2-0016) with AAA mutation and P329G LALA mutation SEQ ID NO: twenty one kappa light chain constant region SEQ ID NO: twenty two λ light chain constant region SEQ ID NO: twenty three Constant region of heavy chain derived from IgG1 SEQ ID NO: twenty four Human vascular endothelial growth factor (VEGF); human VEGF165 precursor sequence SEQ ID NO: 25 Human Angiopoietin-2 (ANG-2) SEQ ID NO: 26 Human Angiopoietin-1 (ANG-1) SEQ ID NO: 27 Human Tie-2 receptor

In the following , examples of the present invention are listed: 1. A bispecific antibody (or a drug containing the bispecific antibody) that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) Or a pharmaceutical formulation, or a bispecific antibody for the preparation of a drug) for the treatment of ocular vascular diseases selected from neovascular AMD (nAMD) and diabetic macular edema (DME) or for the treatment of patients suffering from neovascularization Patients with ocular vascular disease such as AMD (nAMD) and diabetic macular edema (DME), where the treatment includes a personalized treatment interval (PTI). 2. The bispecific antibody (for use) (drug or pharmaceutical formulation) as in Example 1, which is used to treat neovascular age-related macular degeneration (nAMD) or patients suffering from nAMD. 3. The bispecific antibody (for use) (drug or pharmaceutical formulation) as in Example 2, wherein the treatment includes a personalized treatment interval, wherein a) the patient first uses the drug at every 4 weeks (Q4W) dosing interval The bispecific VEGF/ANG2 antibody was treated 4 times; b) The disease activity was assessed at the 20th week and the 24th week, and whether the disease activity was determined to meet one of the following criteria: i) The average of the previous two scheduled visits Compared with the CST value, the central retinal thickness (CST) of the macula increases> 50 μm, the 20th week assessment is for the 12th and 16th week visits and the 24th week assessment is for the 16th and 20th visits, or ii) Compared with the lowest CST value recorded during any of the two previous scheduled visits, the CST increased by ≥ 75 μm; BCVA decreased by ≥ 5 letters compared to the best corrected visual acuity (BCVA) value, iv) Due to nAMD disease activity, compared with the highest BCVA value recorded during any of the two previous scheduled visits, the BCVA decreased by ≥ 10 letters, or v) New macular hemorrhage due to nAMD activity c) Next patient i) Patients who meet the criteria for disease activity at week 20 will be treated with Q8W dosing interval starting from week 20 (wherein at week 20 Perform the first Q8W administration); ii) Patients who meet the criteria for disease activity in the 24th week will be treated with Q12W dosing intervals from the 24th week (where the first Q12W dosing is performed at the 24th week); And iii) Patients who do not meet the disease activity criteria at the 20th and 24th weeks will be treated with Q16W dosing intervals starting from the 28th week (where the first Q16W dosing will be given at the 28th week). 4. The bispecific antibody (for use) (drug or pharmaceutical formulation) of Example 3, wherein after the 60th week, the personalized treatment interval will be extended, shortened or maintained, where a) meets all the following criteria In this case, the interval is extended by 4 weeks (to the maximum Q16W): i) Compared with the average of the last 2 study drug administration visits, the CST is stable. Stability is defined as the CST change less than 30 µm and the lowest Compared with the measured value of the drug administration visit in the study, the CST did not increase by ≥ 50 µm, ii) Compared with the average of the last two study drug administration visits, the BCVA did not decrease by ≥ 5 letters, and was compared with the highest Compared with the drug administration visit measurement value in the study, BCVA did not decrease by ≥ 10 letters, iii) no new macular hemorrhage; b) The interval was shortened by 4 weeks (to Minimum Q8W), or if two or more of the following criteria are met or one criterion includes new macular hemorrhage, the interval is shortened to 8 weeks: i) Compared with the average of the two most recent dosing visits, CST increase ≥ 50 µm, or CST increase ≥ 75 µm compared to the lowest dosing visit measurement, ii) BCVA decrease ≥ 5 letters compared to the average of the two most recent dosing visits, or Compared with the highest dosing visit measurement value, BCVA decreased by ≥ 10 letters, iii) new macular hemorrhage. 5. The bispecific antibody (for use) (drug or pharmaceutical formulation) as in Example 1, which is used to treat diabetic macular edema (DME) or patients suffering from DME. 6. The bispecific antibody (for use) (drug or pharmaceutical formulation) as in Example 5, wherein the treatment includes a personalized treatment interval (PTI), wherein a) the patient is first administered every 4 weeks (Q4W) , Use the bispecific VEGF/ANG2 antibody for treatment until the central retinal thickness (CST) of the macula meets the predetermined reference CST threshold (for Spectralis spectrum domain central retinal thickness SD-OCT, CST <325 µm, or for Cirrus SD-OCT or Topcon SD-OCT, CST<315 µm) (as measured on or after the 12th week); b) The dosing interval is then increased by 4 weeks to the initial Q8W dosing interval; c) From now on , According to the assessments performed during the dosing visits, the dosing interval is extended, shortened or maintained, and the assessments are based on the relative comparison of the CST and best corrected visual acuity (BCVA) with the respective reference CST and BCVA Change; where i) the interval is extended by 4 weeks in the following cases,-the CST value increases or decreases by ≤ 10%, and there is no related BCVA decrease by ≥ 10 letters; ii) the interval is maintained under the following circumstances:- The CST decrease> 10%, or-the CST value increases or decreases ≤ 10%, and the associated BCVA decrease is ≥ 10 letters, or-the CST value increases> 10% and ≤ 20%, and there is no related BCVA decrease ≥ 5 letters; iii) In the following cases, the interval is shortened by 4 weeks-the CST value increases> 10% and ≤ 20%, and the associated BCVA declines ≥ 5 to <10 letters; or-the CST value increases> 20 % Without relevant BCVA decrease ≥ 10 letters; iv) When the CST value increases> 10%, accompanied by a related BCVA decrease ≥ 10 letters, the interval is shortened by 8 weeks; among them, when the initial CST is met In the limit criteria, the respective reference macular center retinal thickness (CST) is the CST value, and the reference CST is adjusted when the CST is reduced by> 10% from the previous reference CST of two consecutive dosing visits. The obtained values are within 30 µm, so that the CST value obtained at a subsequent visit will serve as the new reference CST; and the reference best corrected visual acuity (BCVA) is the one obtained at any previous dosing visit The average of the three best BCVA scores. 7. The bispecific antibody (for use) (drug or pharmaceutical formulation) of Example 6, wherein the dosing interval can be adjusted in a 4-week increment, to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. 8. A bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2), which is used for the treatment of secondary to central retinal vein occlusion, secondary to semi-retinal Vein occlusion or macular edema secondary to branch vein occlusion or treatment of ocular vascular disease selected from the group of ocular edema secondary to central retinal vein occlusion, semiretinal vein occlusion or macular edema secondary to branch vein occlusion Patients with vascular diseases, where the treatment includes a personalized treatment interval (PTI), where a) the patient first uses the bispecific VEGF/ANG2 antibody at a dosing interval of every 4 weeks (Q4W) from day 1 to week 20 Treat; b) From the 24th week, the patient receives the bispecific VEGF/ANG2 antibody at the Q4W frequency until the central macular retinal thickness (CST) meets the predetermined reference CST threshold (for the Spectralis spectrum domain macular central retinal thickness) SD-OCT, CST <325 µm, or for Cirrus SD-OCT or Topcon SD-OCT, CST <315 µm) (as measured at or after the 24th week); c) From now on, based on The evaluations made during the drug visit to extend, shorten or maintain the dosing interval are based on the relative changes of the CST and best corrected visual acuity (BCVA) compared with the respective reference CST and BCVA; where i) in In the following cases, if the interval is extended for 4 weeks, the CST value increases or decreases by ≤ 10%, and there is no related BCVA decrease by ≥ 10 letters; or ii) the interval is maintained if any of the following criteria is met: The CST value Decrease ＞ 10%; or the CST value decrease ≤ 10%, accompanied by the relevant BCVA decrease ≥ 10 letters, or the CST value increase ＞ 10% and ≤ 20%, without the relevant BCVA decrease ≥ 5 letters; iii) If any of the following criteria is met, the interval is shortened by 4 weeks: The CST value increases by> 10% and ≤ 20%, and the associated BCVA decrease is ≥ 5 to <10 letters, or the CST value increases by> 20%, And there is no related BCVA decrease ≥ 10 letters; or the CST value increase ≤ 10%, accompanied by a related BCVA decrease ≥ 10 letters; iv) In the following cases, the interval is shortened to Q4W The CST value increases ＞ 10%, Concomitant BCVA decrease ≥ 10 letters, in which, when the initial CST threshold is met, the central retinal thickness (CST) of the macula is referred to as the CST value, and the CST is relative to the two consecutive dosing visits. Adjust the reference CST when the previous reference CST is reduced by> 10%, and the obtained values are within 30 µm, so that the CST value obtained during subsequent visits will serve as the new reference CST; Best corrected vision (B CVA) is the average of the three best BCVA scores obtained at any previous dosing visit. 9. The bispecific antibody (for use) (drug or pharmaceutical formulation) of Example 8, wherein the dosing interval can be adjusted to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. 10. The bispecific antibody (for use) (drug or pharmaceutical formulation) according to any one of embodiments 1 to 9, wherein the bispecific antibody that binds to human VEGF and human ANG2 is a bispecific bivalent antibody A VEGF/ANG2 antibody comprising a first antigen binding site that specifically binds to human VEGF and a second antigen binding site that specifically binds to human ANG-2, wherein i) the first antigen that specifically binds to VEGF The binding site includes the CDR3H region of SEQ ID NO: 1, the CDR2H region of SEQ ID NO: 2 and the CDR1H region of SEQ ID NO: 3 in the heavy chain variable domain, and includes SEQ ID NO in the light chain variable domain. : The CDR3L region of 4, the CDR2L region of SEQ ID NO: 5, and the CDR1L region of SEQ ID NO: 6; and ii) the second antigen binding site that specifically binds to ANG-2 is comprised in the heavy chain variable domain The CDR3H region of SEQ ID NO: 9, the CDR2H region of SEQ ID NO: 10, and the CDR1H region of SEQ ID NO: 11, and the CDR3L region of SEQ ID NO: 12 and SEQ ID NO: 13 are included in the light chain variable domain. The CDR2L region of SEQ ID NO: 14 and the CDR1L region of SEQ ID NO: 14, and iii) the bispecific antibody comprises the constant heavy chain region of the human IgG1 subclass, which contains the mutations I253A, H310A and H435A and the mutations L234A, L235A and P329G (according to Kabat's EU index number). 11. The bispecific antibody (for use) (drug or pharmaceutical formulation) of embodiment 10, wherein i) the first antigen binding site specifically binding to VEGF comprises the amino acid sequence of SEQ ID NO: 7 As the heavy chain variable domain VH, and comprising the amino acid sequence of SEQ ID NO: 8 as the light chain variable domain VL, and ii) the second antigen binding site that specifically binds to ANG-2 comprises SEQ ID NO The amino acid sequence of: 15 is used as the heavy chain variable domain VH, and the amino acid sequence of SEQ ID NO: 16 is included as the light chain variable domain VL. 12. The bispecific antibody (for use) (drug or pharmaceutical formulation) according to any one of embodiments 1 to 9, wherein the bispecific antibody binding to human VEGF and human ANG2 comprises SEQ ID NO: 17, The amino acid sequences of SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20. 13. The bispecific antibody (for use) (drug or pharmaceutical formulation) according to any one of embodiments 1 to 9, wherein the bispecific antibody is flucipilimab. 14. The bispecific antibody (for use) (drug or pharmaceutical formulation) according to any one of embodiments 10 to 13, wherein the bispecific antibody system is used in a dose of about 5 to 7 mg (in each treatment ) Investment. 15. The bispecific antibody (for use) (drug or pharmaceutical formulation) of any one of embodiments 8 to 13, wherein the bispecific antibody system is administered at a dose of about 6 mg (at each treatment) versus. 16. The bispecific antibody (for use) (drug or pharmaceutical formulation) according to any one of embodiments 14 to 15, wherein the bispecific antibody system is administered at a concentration of about 120 mg/ml. 17. The bispecific antibody (for use) (drug or pharmaceutical formulation) according to any one of the preceding embodiments, wherein the patient suffering from ocular vascular disease has not been previously treated with anti-VEGF therapy. 18. The bispecific antibody (for use) (drug or pharmaceutical formulation) according to any one of the preceding embodiments, wherein the patient suffering from ocular vascular disease has been previously treated with anti-VEGF therapy. 19. The bispecific antibody (for use) (drug or pharmaceutical formulation) according to any one of the preceding embodiments, wherein the antibody system is administered according to the measurement of the software tool. 20. A method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for the treatment of a patient suffering from nAMD, the method comprising: receiving patient data in a computing system, the patient data including the patient’s CST and most Best corrected visual acuity (BCVA) and, as appropriate, information about the assessment of new macular hemorrhage; and use the calculation system to extend, shorten or maintain dosing based on the received patient data compared with the respective reference CST and BCVA Interval; and PTI is obtained according to the dosing interval, where a) The interval is extended by 4 weeks (to the maximum Q16W) if all the following criteria are met: i) The average value of the last 2 study drug administration visits CST is stable, where stability is defined as CST change less than 30 µm and no increase in CST ≥ 50 µm compared to the lowest study drug administration visit measurement value, ii) Compared with the last two study drug administrations Compared with the average of the visits, BCVA did not decrease by ≥ 5 letters, and compared with the highest survey value of drug administration in the study, BCVA did not decrease by ≥ 10 letters, iii) no new macular hemorrhage b) the The interval is shortened by 4 weeks if one of the following criteria is met (to a minimum Q8W), or if two or more of the following criteria are met or one of the criteria includes new macular hemorrhage, shortened to 8 weeks Interval: i) Compared with the average of the last two dosing visits, the CST increased by ≥ 50 µm, or compared with the lowest dosing visit measurement value, the CST increased by ≥ 75 µm; ii) Compared with the last two visits Compared with the average value of the dosing visit, the BCVA decreased by ≥ 5 letters, or compared with the highest dosing visit measurement value, the BCVA decreased by ≥ 10 letters; iii) New macular hemorrhage. 21. A method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for the treatment of a patient suffering from DME, the method comprising: receiving patient data in a computing system, the patient data including the patient's CST and most Best corrected visual acuity (BCVA); and using the calculation system to extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; and obtain the PTI according to the dosing interval, where i ) In the following cases, the interval is extended by 4 weeks,-the CST value increases or decreases by ≤ 10%, and there is no related BCVA decrease by ≥ 10 letters; ii) The interval is maintained in the following cases:-the CST decreases> 10%, or-the CST value increased or decreased by ≤ 10%, and the associated BCVA decrease was ≥ 10 letters, or-the CST value increased by ＞ 10% and ≤ 20%, and there was no related BCVA decrease of ≥ 5 letters; iii) In the following cases, the interval is shortened by 4 weeks-the CST value has increased by> 10% and ≤ 20%, with associated BCVA decrease of ≥ 5 to <10 letters; or-the CST value has increased by> 20% without Related BCVA decrease ≥ 10 letters; iv) In the case of a CST value increase> 10%, accompanied by a related BCVA decrease ≥ 10 letters, the interval is shortened by 8 weeks. 22. A method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for the treatment of patients suffering from ocular vascular disease, the ocular vascular disease selected from secondary to central retinal vein occlusion, secondary For semiretinal vein occlusion or macular edema secondary to branch vein occlusion, the method includes: receiving patient data in a computing system, the patient data including the patient’s CST and best corrected visual acuity (BCVA); and using the computing system based on Compare the received patient data with reference to CST and BCVA respectively, extend, shorten or maintain the dosing interval; and obtain the PTI according to the dosing interval, where i) In the following cases, the interval is extended by 4 weeks for the CST value Increase or decrease by ≤ 10% without related BCVA decrease by ≥ 10 letters; or ii) Maintain the interval if one of the following criteria is met: The CST value decreases>10%; or the CST value decreases ≤ 10 %, the associated decrease in BCVA is ≥ 10 letters, or the CST value increases ＞ 10% and ≤ 20%, and there is no relevant decrease in BCVA ≥ 5 letters; iii) In the case of meeting any of the following criteria, the interval Shortened by 4 weeks: The CST value increased by> 10% and ≤ 20%, with a related BCVA decrease of ≥ 5 to <10 letters, or the CST value increased by> 20% without a related BCVA decrease of ≥ 10 letters, or The CST value increased by ≤ 10%, and the associated BCVA decrease was ≥ 10 letters; iv) In the following cases, the interval was shortened to Q4W The CST value increased by> 10%, and the associated BCVA decreased by ≥ 10 letters. 23. The method of any one of embodiments 20, 21, or 22, further comprising: receiving updated patient data in the computing system; using the computing system to continuously update or maintain the patient data based on the updated patient data Medication interval; and based on the updated or maintained dosing interval, a visualized result, user interface, or notification is generated. 24. A use of personalized dosing schedule based on personalized treatment interval (PTI) (for the treatment of nAMD), where the computing system obtains the PTI by: Receive patient data in the computing system, and the patient data contains the patient's CST And best corrected visual acuity (BCVA) and, as appropriate, information on the assessment of new macular hemorrhage; and based on the received patient data compared with the respective reference CST and BCVA, to extend, shorten or maintain the dosing interval; a) When all the following criteria are met, the interval is extended by 4 weeks (to a maximum of Q16W): i) Compared with the average of the last 2 study drug administration visits, the CST is stable, where stability is defined as CST The change is less than 30 µm and the CST does not increase ≥ 50 µm compared with the lowest study drug administration visit measurement value, ii) Compared with the average of the two most recent study drug administration visits, the BCVA does not decrease ≥ 5 letters, and compared with the highest drug administration visit measurement value in the study, BCVA did not decrease by ≥ 10 letters, iii) no new macular hemorrhage b) The interval is in the case of one of the following criteria , Shortened to 4 weeks (to a minimum of Q8W), or shortened to 8 weeks if two or more of the following criteria are met or one of the criteria includes new macular hemorrhage: i) and the two most recent dosing visits Compared with the average value, CST increased by ≥ 50 µm, or compared with the lowest dosing visit measurement value, CST increased by ≥ 75 µm; ii) Compared with the average of the last two dosing visits, BCVA decreased ≥ 5 letters, or BCVA decrease ≥ 10 letters compared with the highest dosing visit measurement; iii) new macular hemorrhage. 25. A use of personalized dosing schedule based on personalized treatment interval (PTI) (for the treatment of DME), in which the computing system obtains the PTI by: Receive patient data, which includes the patient’s CST and the best Corrected visual acuity (BCVA); and extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; where i) the interval is extended by 4 weeks in the following cases,-the CST The value increase or decrease is ≤ 10%, and there is no relevant BCVA decrease ≥ 10 letters; ii) The interval is maintained under the following conditions:-the CST decrease> 10%, or-the CST value increase or decrease ≤ 10%, The associated decrease in BCVA is ≥ 10 letters, or-the CST value has increased by> 10% and ≤ 20%, and there is no associated decrease in BCVA by ≥ 5 letters; iii) In the following cases, the interval is shortened by 4 weeks-the CST Value increase> 10% and ≤ 20%, with related BCVA decrease ≥ 5 to <10 letters; or-The CST value increase> 20% without related BCVA decrease ≥ 10 letters; iv) At the CST value In the case of an increase of> 10%, and the associated decrease in BCVA of ≥ 10 letters, the interval is shortened by 8 weeks. 26. A use of personalized medication schedule based on personalized treatment interval (PTI) (for the treatment of macular edema secondary to central retinal vein occlusion, secondary to semiretinal vein occlusion, or secondary to branch vein occlusion) , Where the computing system obtains the PTI by: receiving patient data, which includes the patient’s CST and best corrected visual acuity (BCVA); and based on the received patient data compared with the respective reference CST and BCVA, extending, Shorten or maintain the dosing interval; where i) In the following cases, the interval is extended for 4 weeks, the CST value increases or decreases by ≤ 10%, and there is no related BCVA decrease ≥ 10 letters; or ii) in compliance with any of the following criteria In the case of, maintain the interval: the CST value decreases>10%; or the CST value decreases ≤ 10%, and the associated BCVA decreases ≥ 10 letters, or the CST value increases> 10% and ≤ 20%, without Related BCVA decrease ≥ 5 letters; iii) If any of the following criteria is met, the interval is shortened by 4 weeks: The CST value increases> 10% and ≤ 20%, accompanied by a related BCVA decrease ≥ 5 to <10 Letters, or the CST value increased by> 20% without a related BCVA decrease of ≥ 10 letters, or the CST value increased by ≤ 10%, accompanied by a related BCVA decrease of ≥ 10 letters; iv) In the following cases, the interval Shortened to Q4W The CST value increased by> 10%, and the associated BCVA decreased by ≥ 10 letters.

In the following, examples of the present invention are listed: 1. A method for treating patients suffering from ocular vascular diseases selected from neovascular AMD (nAMD) and diabetic macular edema (DME), the method comprising administering to the patient an effective amount of human vascular endothelial growth factor ( VEGF) and human angiopoietin-2 (ANG-2) bispecific antibody, wherein the treatment includes a personalized treatment interval (PTI). 2. The method of embodiment 1, wherein the ocular vascular disease is neovascular age-related macular degeneration (nAMD). 3. The method of embodiment 2, wherein the treatment includes a personalized treatment interval, wherein a) The patient is first treated with the bispecific VEGF/ANG2 antibody for 4 times at a dosing interval every 4 weeks (Q4W); b) Assessment of disease activity at the 20th and 24th week, in which the determination of whether the disease activity meets one of the following criteria: i) Compared with the average CST value of the two previous scheduled visits, the central retinal thickness (CST) of the macula has increased> 50 μm. The 20th week assessment is for the 12th and 16th week visits and the 24th week assessment system For visits in weeks 16 and 20, or ii) Compared with the lowest CST value recorded during any of the two previous scheduled visits, the CST increased by ≥ 75 μm; iii) Due to nAMD disease activity, BCVA decreased by ≥ 5 letters compared with the average best corrected visual acuity (BCVA) value of the two previous scheduled visits, iv) Due to nAMD disease activity, the BCVA decreased by ≥ 10 letters compared to the highest BCVA value recorded during any of the two previous scheduled visits, or v) New macular hemorrhage due to nAMD activity c) Follow the patient i) Patients who meet the criteria for disease activity in the 20th week will be treated with Q8W dosing intervals from the 20th week (the first Q8W dosing will be given at the 20th week); ii) Patients who meet the criteria for disease activity at week 24 will be treated with Q12W dosing intervals from week 24 (where the first Q12W dosing will be given at week 24); and iii) Patients who do not meet the criteria for disease activity in the 20th and 24th weeks will be treated at the Q16W dosing interval from the 28th week (the first Q16W dosing will be given at the 28th week). 4. The method of embodiment 3, wherein after the 60th week, the personalized treatment interval will be extended, shortened or maintained, wherein a) When all the following criteria are met, the interval is extended by 4 weeks (to the maximum Q16W): i) Compared with the average value of the last two study drug administration visits, CST is stable. Stability is defined as the change of CST less than 30 µm and compared with the lowest measured value of the drug administration visit in the study, CST No increase ≥ 50 µm, ii) Compared with the average of the last two study drug administration visits, BCVA did not decrease by ≥ 5 letters, and compared with the highest study drug administration visit measurement value, BCVA did not decrease by ≥ 10 letters , iii) No new macular hemorrhage; b) the interval In the case of meeting one of the following criteria, shorten 4 weeks (to a minimum of Q8W), or In the event that two or more of the following criteria are met or one criterion includes new macular hemorrhage, shorten the interval to 8 weeks: i) Compared with the average of the last two dosing visits, the CST increased by ≥ 50 µm, or compared with the lowest dosing visit measurement value, the CST increased by ≥ 75 µm, ii) Compared with the average of the last two dosing visits, the BCVA decreased by ≥ 5 letters, or compared with the highest dosing visit measurement value, the BCVA decreased by ≥ 10 letters, iii) New macular hemorrhage. 5. As in the method of Example 1, it is used to treat diabetic macular edema (DME) or patients suffering from DME. 6. The method of embodiment 5, wherein the treatment includes a personalized treatment interval (PTI), wherein a) The patient is first treated with the bispecific VEGF/ANG2 antibody at a dosing interval of 4 weeks (Q4W) until the central retinal thickness (CST) of the macula meets the predetermined reference CST threshold (for the Spectralis spectrum macular center Retina thickness SD-OCT, CST <325 µm, or for Cirrus SD-OCT or Topcon SD-OCT, CST <315 µm) (as measured on or after the 12th week); b) The dosing interval is then increased by 4 weeks to the initial Q8W dosing interval; c) From now on, extend, shorten or maintain the dosing interval based on the assessments performed during the dosing visits based on the CST and best corrected visual acuity (BCVA) and the respective reference CST and BCVA Relative change in comparison; among them i) In the following cases, the interval is extended by 4 weeks, -The CST value increased or decreased by ≤ 10%, and there is no related BCVA decrease by ≥ 10 letters; ii) Maintain this interval in the following cases: -The CST reduction> 10%, or -The CST value increased or decreased by ≤ 10%, and the associated BCVA decreased by ≥ 10 letters, or -The CST value increased> 10% and ≤ 20%, and there is no related BCVA decrease ≥ 5 letters; iii) In the following cases, the interval is shortened by 4 weeks -The CST value increased by> 10% and ≤ 20%, with the associated decrease in BCVA by ≥ 5 to <10 letters; or -The CST value increased by ＞ 20%, and there is no related BCVA decrease by ≥ 10 letters; iv) In the case where the CST value increases> 10%, and the related BCVA decreases ≥ 10 letters, the interval is shortened by 8 weeks; Among them, when the initial CST threshold is met, the respective reference macular central retinal thickness (CST) is the CST value, and the CST is reduced by> 10% compared to the previous reference CST of two consecutive dosing visits Adjust the reference CST, and the obtained values are within 30 µm, so that the CST value obtained during subsequent visits will serve as the new reference CST; and The reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any previous dosing visit. 7. The method as in Example 6, wherein the dosing interval can be adjusted in a 4-week increase to the maximum every 16 weeks (Q16W) and the minimum Q4W. 8. A method for treating patients suffering from ocular vascular disease, the ocular vascular disease selected from the group consisting of macular edema secondary to central retinal vein occlusion, secondary hemiretinal vein occlusion or branch vein occlusion, the method comprising An effective amount of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) is administered to the patient, wherein the treatment includes a personalized treatment interval (PTI), wherein a) The patient is first treated with the bispecific VEGF/ANG2 antibody at a dosing interval of 4 weeks (Q4W) from day 1 to week 20; b) From the 24th week, the patient receives the bispecific VEGF/ANG2 antibody at the Q4W frequency until the central macular retinal thickness (CST) meets the predetermined reference CST threshold (for the Spectralis spectrum domain macular central retinal thickness SD-OCT , CST <325 µm, or for Cirrus SD-OCT or Topcon SD-OCT, CST <315 µm) (as measured on or after the 24th week); c) From now on, extend, shorten or maintain the dosing interval based on the assessments performed during the dosing visits based on the CST and best corrected visual acuity (BCVA) and the respective reference CST and BCVA Relative change in comparison; among them i) In the following cases, the interval is extended by 4 weeks The CST value increased or decreased by ≤ 10% without a related BCVA decrease by ≥ 10 letters; or ii) Maintain this interval if any of the following criteria is met: The CST value is reduced by> 10%; or The CST value is reduced by ≤ 10%, with associated BCVA reduction by ≥ 10 letters, or The CST value increased by more than 10% and less than 20%, and there is no related BCVA decreased by more than 5 letters; iii) If any of the following criteria is met, the interval is shortened by 4 weeks: The CST value increased by> 10% and ≤ 20%, with associated BCVA decrease by ≥ 5 to <10 letters, or The CST value increased by> 20% without a related decrease in BCVA by ≥ 10 letters; or The CST value increased by ≤ 10%, and the associated BCVA decreased by ≥ 10 letters; iv) In the following cases, the interval is shortened to Q4W The CST value increased by> 10%, and the associated BCVA decreased by ≥ 10 letters, Among them, when the initial CST threshold is met, the respective reference macular central retinal thickness (CST) is the CST value, and the CST is reduced by> 10% compared to the previous reference CST of two consecutive dosing visits Adjust the reference CST, and the obtained values are within 30 µm, so that the CST value obtained during subsequent visits will serve as the new reference CST; and The reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any previous dosing visit. 9. The method as in embodiment 8, wherein the dosing interval can be adjusted to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. 10. As the method of any one of embodiments 1 to 9, wherein the bispecific antibody that binds to human VEGF and human ANG2 is a bispecific bivalent anti-VEGF/ANG2 antibody, which includes a bispecific antibody that specifically binds to human VEGF The first antigen binding site and the second antigen binding site specifically bound to human ANG-2, wherein i) The first antigen binding site that specifically binds to VEGF includes the CDR3H region of SEQ ID NO: 1, the CDR2H region of SEQ ID NO: 2, and the CDR1H region of SEQ ID NO: 3 in the heavy chain variable domain, And the light chain variable domain includes the CDR3L region of SEQ ID NO: 4, the CDR2L region of SEQ ID NO: 5, and the CDR1L region of SEQ ID NO: 6; and ii) The second antigen binding site that specifically binds to ANG-2 includes the CDR3H region of SEQ ID NO: 9, the CDR2H region of SEQ ID NO: 10, and the CDR1H of SEQ ID NO: 11 in the heavy chain variable domain Region, and includes the CDR3L region of SEQ ID NO: 12, the CDR2L region of SEQ ID NO: 13 and the CDR1L region of SEQ ID NO: 14 in the light chain variable domain, And where iii) The bispecific antibody contains the constant heavy chain region of the human IgG1 subclass, which contains the mutations I253A, H310A and H435A and the mutations L234A, L235A and P329G (numbered according to the EU index of Kabat). 11. As in the method of embodiment 10, where i) The first antigen binding site that specifically binds to VEGF includes the amino acid sequence of SEQ ID NO: 7 as the heavy chain variable domain VH, and includes the amino acid sequence of SEQ ID NO: 8 as the light chain Variable domain VL, and ii) The second antigen binding site that specifically binds to ANG-2 includes the amino acid sequence of SEQ ID NO: 15 as the heavy chain variable domain VH, and includes the amino acid sequence of SEQ ID NO: 16 as the light Chain variable domain VL. 12. The method according to any one of embodiments 1 to 9, wherein the bispecific antibody that binds to human VEGF and human ANG2 comprises SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 amino acid sequence. 13. As in the method of any one of embodiments 1 to 9, wherein the bispecific antibody is flucipilimab. 14. The method as in any one of embodiments 10 to 13, wherein the bispecific antibody is administered in a dose of about 5 to 7 mg (at each treatment). 15. The method as in any one of embodiments 10 to 13, wherein the bispecific antibody is administered in a dose of about 6 mg (at each treatment). 16. As in the method of any one of embodiments 14 to 15, wherein the bispecific antibody is administered at a concentration of about 120 mg/ml. 17. The method as in any one of the preceding embodiments, wherein the patient suffering from ocular vascular disease has not been previously treated with anti-VEGF therapy. 18. The method as in any one of the preceding embodiments, wherein the patient suffering from ocular vascular disease has been previously treated with anti-VEGF therapy. 19. The method as in any one of the preceding embodiments, wherein the anti-system is administered according to the measurement of the software tool. 20. A method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for the treatment of patients suffering from nAMD, the method includes: Receive patient data in the computing system, the patient data includes the patient's CST and best corrected visual acuity (BCVA), as well as optional information about the assessment of new macular hemorrhage; and Use this calculation system to extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; and PTI is obtained according to the dosing interval, where a) When all the following criteria are met, the interval is extended by 4 weeks (to the maximum Q16W): i) Compared with the average value of the last two study drug administration visits, CST is stable. Stability is defined as the change of CST less than 30 µm and compared with the lowest measured value of the drug administration visit in the study, CST No increase ≥ 50 µm, ii) Compared with the average of the last two study drug administration visits, BCVA did not decrease by ≥ 5 letters, and compared with the highest study drug administration visit measurement value, BCVA did not decrease by ≥ 10 letters , iii) No new macular hemorrhage b) the interval In the case of meeting one of the following criteria, shorten 4 weeks (to a minimum of Q8W), or In the event that two or more of the following criteria are met or one criterion includes new macular hemorrhage, shorten the interval to 8 weeks: i) Compared with the average of the last two dosing visits, the CST increased by ≥ 50 µm, or compared with the lowest dosing visit measurement value, the CST increased by ≥ 75 µm; ii) Compared with the average of the last two dosing visits, the BCVA decreased by ≥ 5 letters, or compared with the highest dosing visit measurement value, the BCVA decreased by ≥ 10 letters; iii) New macular hemorrhage. 21. A method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for the treatment of patients suffering from DME, the method includes: Receive patient data in the computing system, which includes the patient's CST and best corrected visual acuity (BCVA); and Use this calculation system to extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; and PTI is obtained according to the dosing interval, where i) In the following cases, the interval is extended by 4 weeks, -The CST value increased or decreased by ≤ 10%, and there is no related BCVA decrease by ≥ 10 letters; ii) Maintain this interval in the following cases: -The CST reduction> 10%, or -The CST value increased or decreased by ≤ 10%, and the associated BCVA decreased by ≥ 10 letters, or -The CST value increased> 10% and ≤ 20%, and there is no related BCVA decrease ≥ 5 letters; iii) In the following cases, the interval is shortened by 4 weeks -The CST value increased by> 10% and ≤ 20%, with the associated decrease in BCVA by ≥ 5 to <10 letters; or -The CST value increased by ＞ 20%, and there is no related BCVA decrease by ≥ 10 letters; iv) When the CST value increases> 10%, and the associated BCVA decreases ≥ 10 letters, the interval is shortened by 8 weeks. 22. A method for providing a personalized drug delivery schedule based on a personalized treatment interval (PTI) for the treatment of patients suffering from ocular vascular disease, which is selected from secondary to central retinal vein occlusion, secondary For semiretinal vein occlusion or macular edema secondary to branch vein occlusion, the method includes: Receive patient data in the computing system, which includes the patient's CST and best corrected visual acuity (BCVA); and Use this calculation system to extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; and PTI is obtained according to the dosing interval, where i) In the following cases, the interval is extended by 4 weeks The CST value increased or decreased by ≤ 10% without a related BCVA decrease by ≥ 10 letters; or ii) Maintain this interval if any of the following criteria is met: The CST value is reduced by> 10%; or The CST value is reduced by ≤ 10%, with associated BCVA reduction by ≥ 10 letters, or The CST value increased by more than 10% and less than 20%, and there is no related BCVA decreased by more than 5 letters; iii) If any of the following criteria is met, the interval is shortened by 4 weeks: The CST value increased by> 10% and ≤ 20%, with associated BCVA decrease by ≥ 5 to <10 letters, or The CST value increased by> 20% without a related decrease in BCVA by ≥ 10 letters, or The CST value increased by ≤ 10%, and the associated BCVA decreased by ≥ 10 letters; iv) In the following cases, the interval is shortened to Q4W The CST value increased by> 10%, and the associated BCVA decreased by ≥ 10 letters. 23. Such as the method in any one of Embodiments 20, 21 or 22, which further includes: Receive updated patient data in the computing system; Use the computing system to continuously update or maintain the dosing interval based on the updated patient data; and Based on the updated or maintained dosing interval, a visualized result, user interface, or notification is generated. 24. A use of personalized medication scheduling based on personalized treatment interval (PTI) (for the treatment of nAMD), in which the computing system obtains the PTI through the following: Receive patient data in the computing system, the patient data includes the patient's CST and best corrected visual acuity (BCVA), as well as optional information about the assessment of new macular hemorrhage; and Extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; among them a) When all the following criteria are met, the interval is extended by 4 weeks (to the maximum Q16W): i) Compared with the average value of the last two study drug administration visits, CST is stable. Stability is defined as the change of CST less than 30 µm and compared with the lowest measured value of the drug administration visit in the study, CST No increase ≥ 50 µm, ii) Compared with the average of the last two study drug administration visits, BCVA did not decrease by ≥ 5 letters, and compared with the highest study drug administration visit measurement value, BCVA did not decrease by ≥ 10 letters , iii) No new macular hemorrhage b) the interval In the case of meeting one of the following criteria, shorten 4 weeks (to a minimum of Q8W), or In the event that two or more of the following criteria are met or one criterion includes new macular hemorrhage, shorten the interval to 8 weeks: i) Compared with the average of the two most recent dosing visits, the CST increased by ≥ 50 µm, or compared with the lowest dosing visit measurement value, the CST increased by ≥ 75 µm; ii) Compared with the average of the last two dosing visits, the BCVA decrease is ≥ 5 letters, or compared with the highest dosing visit measurement value, the BCVA decreases ≥ 10 letters; iii) New macular hemorrhage. 25. A use of personalized medication scheduling based on personalized treatment interval (PTI) (for the treatment of DME), where the computing system obtains the PTI through the following: Receive patient data, which includes the patient's CST and best corrected visual acuity (BCVA); and Extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; among them i) In the following cases, the interval is extended by 4 weeks, -The CST value increased or decreased by ≤ 10%, and there is no related BCVA decrease by ≥ 10 letters; ii) Maintain this interval in the following cases: -The CST reduction> 10%, or -The CST value increased or decreased by ≤ 10%, and the associated BCVA decreased by ≥ 10 letters, or -The CST value increased> 10% and ≤ 20%, and there is no related BCVA decrease ≥ 5 letters; iii) In the following cases, the interval is shortened by 4 weeks -The CST value increased by> 10% and ≤ 20%, with the associated decrease in BCVA by ≥ 5 to <10 letters; or -The CST value increased by ＞ 20%, and there is no related BCVA decrease by ≥ 10 letters; iv) When the CST value increases> 10%, and the associated BCVA decreases ≥ 10 letters, the interval is shortened by 8 weeks. 26. A use of personalized medication scheduling based on personalized treatment interval (PTI) (for the treatment of macular edema secondary to central retinal vein occlusion, secondary to semiretinal vein occlusion, or secondary to branch vein occlusion) , Where the computing system obtains PTI by: Receive patient data, which includes the patient's CST and best corrected visual acuity (BCVA); and Extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; among them i) In the following cases, the interval is extended by 4 weeks The CST value increased or decreased by ≤ 10% without a related BCVA decrease by ≥ 10 letters; or ii) Maintain this interval if any of the following criteria is met: The CST value is reduced by> 10%; or The CST value is reduced by ≤ 10%, with associated BCVA reduction by ≥ 10 letters, or The CST value increased by more than 10% and less than 20%, and there is no related BCVA decreased by more than 5 letters; iii) If any of the following criteria is met, the interval is shortened by 4 weeks: The CST value increased by> 10% and ≤ 20%, with associated BCVA decrease by ≥ 5 to <10 letters, or The CST value increased by> 20% without a related decrease in BCVA by ≥ 10 letters; or The CST value increased by ≤ 10%, and the associated BCVA decreased by ≥ 10 letters; iv) In the following cases, the interval is shortened to Q4W The CST value increased by> 10%, and the associated BCVA decreased by ≥ 10 letters.

Example Treatment of patients suffering from vascular ophthalmopathy with bispecific antibodies that bind to human VEGF and human ANG2

Example 1: The efficacy and durability of the use of personalized treatment intervals to treat patients suffering from neovascular age-related macular degeneration (nAMD). In particular, the investigation was conducted with RO6867461 (fluxipilimab) administered at 12 and 16 week intervals. In the early phase II, 52-week study of the efficacy in untreated patients with nAMD, some possibilities for longer durability (which may be longer for retreatment) can be found in all participating patients. Study three teams -Team A (Q12W): 6 mg RO6867461 intravitreal (IVT) every 4 weeks until the 12th week (4 injections), followed by 6 mg RO6867461 IVT every 12 weeks, until the 48th week (in the 24th and the 24th week) 36 weeks and 48 weeks injection; 3 injections)…………………………………… -Team B (Q16W): 6 mg RO6867461 (IVT) every 4 weeks until the 12th week (4 injections), then 6 mg RO6867461 IVT every 16 weeks, until the 48th week (at the 28th and 44th weeks) Injection; 2 injections)…………………………………… -Team group C (comparative agent team group): 0.5 mg lambizumab IVT every 4 weeks for 48 weeks (13 injections). Only one eye will be selected as the study eye.

The results on BCVA are shown in Figure 5. Figure 5 shows the combination of bispecific anti-VEGF/ANG2 antibody RO6867461 (fluxipilimab) at 12 and 16 week intervals and lanbizumab (Lucentis®) at intervals of 4 weeks (intravitreal administration at 0.3 mg doses). The increase in BCVA of patients with neovascular age-related macular degeneration (nAMD) compared to baseline.

A follow-up phase III study was started, which will now evaluate the administration of fluxipi at a dose of 6 mg at up to 16-week intervals (by specific personalized treatment interval (PTI) scheduling) compared to aflibercept monotherapy Q8W Efficacy, safety, durability and pharmacokinetics of monoclonal antibodies in patients with CNV secondary to AMD (also known as nAMD). Flucipilimab will be administered at a concentration of approximately 120 mg/ml.

The specific goals and corresponding endpoints of the study are summarized in Table 1. Table 1 Goals and corresponding end points Main efficacy target Corresponding to the end ● To evaluate the efficacy of IVT injection of 6 mg fluxipilimab on BCVA results compared with aflibercept ● Based on the average of the 40th, 44th and 48th week, the change from the baseline BCVA (as measured on the ETDRS chart at a starting distance of 4 meters) Secondary efficacy goal Corresponding to the end ● To evaluate the efficacy of flucipilimab on additional BCVA results ● Change from baseline BCVA over time ● Proportion of patients with an increase of ≥ 15, ≥ 10, ≥ 5, or ≥ 0 letters over time relative to baseline BCVA ● Avoid BCVA loss over time relative to baseline ≥ 15, Proportion of patients with ≥ 10, ≥ 5, or> 0 letters ● Proportion of patients with BCVA Snellen equivalent of 20/40 or better over time ● Increase by ≥ 15 letters or achieve ≥ 84 letters over time The proportion of patients with BCVA ● The proportion of patients with a BCVA Snellen equivalent of 20/200 or worse over time ● To evaluate the frequency of study drug administration ● The proportion of patients who received Q8W, Q12W, and Q16W treatment intervals in the 48th, 60th, and 112th weeks ● The number of study drug injections received throughout the 48th, 60th, and 112th weeks ● To use OCT to evaluate the efficacy of fluxipilimab on the measurement of anatomical results ● Based on the average of the 40th, 44th, and 48th week, the change from baseline CST ● The change from baseline CST over time ● Proportion of patients without intraretinal fluid over time ● Over time Proportion of patients without subretinal fluid ● Proportion of patients with no intraretinal and subretinal fluids over time ● Proportion of patients with no intraretinal cysts over time ● Patients without pigment epithelial detachment over time Ratio of ● To use FFA to evaluate the efficacy of fluxipilimab on the measurement of anatomical results ● Change from the baseline total area of CNV lesions at the 48th and 112th week ● Change from the baseline total area of the leakage at the 48th week and 112th week Table 1 Goals and corresponding end points (continued) Security goals Corresponding to the end ● To assess the ocular and non-ocular safety and tolerability of flucipilimab ● Incidence and severity of ocular adverse events ● Incidence and severity of non-ocular adverse events Exploratory efficacy goal Corresponding to the end ● To use NEI VFQ-25 to evaluate the efficacy of fluxipilimab on patients’ reported vision-related functions and quality of life ● Changes over time relative to the baseline NEI VFQ-25 composite score Pharmacokinetic goals Corresponding to the end ● To characterize the systemic pharmacokinetics of flucipilimab ● Fluxipilimab plasma concentration over time Immunogenic target Corresponding to the end ● To evaluate the immune response to flucipilimab ● To evaluate the potential efficacy of ADA ● Relative to the presence of ADA at baseline. The presence of ADA during the study period ● The relationship between ADA status and efficacy, safety, or PK endpoint Exploratory pharmacokinetics, pharmacodynamics and biomarker targets Corresponding to the end ● To assess the potential relationship between selected covariates and exposure to fluxipilimab ● The relationship between the selected covariates and the concentration of fluxipilimab in plasma or aqueous humor (as appropriate) or PK parameters ● To assess the drug concentration (exposure)-effect relationship without VEGF-A and Ang-2 ● To characterize the pharmacokinetics of fluxipilimab in the humoral fluid (as the case exists) and vitreous (as the case exists) ● The relationship between the pharmacokinetics of fluxipilimab and the concentration of VEGF-A and Ang-2 without VEGF-A and Ang-2 in the ocular fluid (as the case exists), plasma and/or vitreous (as the case exists) over time Concentrations of fluxipilimab in ocular fluid (as the case exists) and vitreous (as the case exists) over time ● To explore the concentration-effect relationship of vision and other endpoints (for example, anatomical markers) ● Changes in the pharmacokinetics of fluxipilimab and BCVA or other endpoints (for example, anatomical markers) over time Table 1 Goals and corresponding end points (continued) Main efficacy target Corresponding to the end ● To evaluate the efficacy of IVT injection of 6 mg fluxipilimab on BCVA results compared with aflibercept ● Based on the average of the 40th, 44th and 48th week, the change from the baseline BCVA (as measured on the ETDRS chart at a starting distance of 4 meters) Secondary efficacy goal Corresponding to the end ● To evaluate the efficacy of flucipilimab on additional BCVA results ● Change from baseline BCVA over time ● Proportion of patients with an increase of ≥ 15, ≥ 10, ≥ 5, or ≥ 0 letters over time relative to baseline BCVA ● Avoid BCVA loss over time relative to baseline ≥ 15, Proportion of patients with ≥ 10, ≥ 5, or> 0 letters ● Proportion of patients with BCVA Snellen equivalent of 20/40 or better over time ● Increase by ≥ 15 letters or achieve ≥ 84 letters over time The proportion of patients with BCVA ● The proportion of patients with a BCVA Snellen equivalent of 20/200 or worse over time ● To evaluate the frequency of study drug administration ● The proportion of patients who received Q8W, Q12W, and Q16W treatment intervals in the 48th, 60th, and 112th weeks ● The number of study drug injections received throughout the 48th, 60th, and 112th weeks ● To use OCT to evaluate the efficacy of fluxipilimab on the measurement of anatomical results ● Based on the average of the 40th, 44th, and 48th week, the change from baseline CST ● The change from baseline CST over time ● Proportion of patients without intraretinal fluid over time ● Over time Proportion of patients without subretinal fluid ● Proportion of patients with no intraretinal and subretinal fluids over time ● Proportion of patients with no intraretinal cysts over time ● Patients without pigment epithelial detachment over time Ratio of ● To use FFA to evaluate the efficacy of fluxipilimab on the measurement of anatomical results ● Change from the baseline total area of CNV lesions at the 48th and 112th week ● Change from the baseline total area of the leakage at the 48th week and 112th week

Patients suffering from neovascular age-related macular degeneration (nAMD) (also known as wet age-related macular degeneration (wet AMD)) are treated with a bispecific antibody that binds to human VEGF and human ANG2. The specific antibody comprises the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 (this antibody VEGFang2-0016 and its production are also described in detail in the reference Into WO2014/009465). The name of this bispecific anti-VEGF/ANG2 antibody herein is RO6867461 or RG7716 or VEGFang2-0016 or flucipilimab. In the treatment, for example, aflibercept will be used as an active comparison agent. Patients include patients who have not been treated with anti-VEGF therapy (not previously treated with anti-VEGF therapy such as afliberx and/or lambizumab and/or other anti-VEGF therapies). Use a sterile, colorless to light brown, preservative-free vial of RO6867461 (fluxipilimab) for intravitreal (IVT) administration at a dose of 6 mg.

Study Design This is a multi-center, randomized, activity comparison agent to study the efficacy, safety, durability, and pharmacokinetics of flucipilimab administered at intervals of up to 16 weeks in untreated patients with nAMD , Double-blind, parallel group, 112-week study.

Approximately 640 patients will be registered globally and randomly assigned to one of the two treatment teams at a ratio of 1:1: Team A (fluxipilimab, up to Q16W) (n=320): Patients randomized to team A will receive Q4W 6 mg IVT fluxipilimab until the 12th week (4 injections). In the 20th week, the disease activity assessment of the protocol definition requires patients in group A with active disease (for guidelines, see below) to be treated at their visit and continue the Q8W dosing schedule of fluxipilimab. The disease activity assessment at the 24th week defined by the second regimen requires patients in group A who have an active disease (excluding patients who have an active disease at the 20th week and therefore receive the Q8W dosing regimen of fluxipilimab Patients) were treated at his visit and continued the Q12W dosing regimen of fluxipilimab. In the 20th and 24th weeks, patients who did not suffer from active disease and received fluxipilimab according to the criteria defined in the regimen will be treated with the Q16W dosing regimen of fluxipilimab. Based on disease activity assessments performed at 20 weeks and 24 weeks, patients will continue to receive fluxipilimab on a fixed schedule every 8 weeks, every 12 weeks, or every 16 weeks until the 60th week. Starting from week 60 (when all patients in team A are scheduled to receive fluxipilimab), all patients in team A will be treated according to the personalized treatment interval (PTI) dosing schedule (about PTI dosing guidelines, see Table 2), until the 108th week. Team B (comparative agent team) (Q8W): Patients randomized to team B will receive Q4W 2 mg IVT Aflibercept until week 8 (3 injections), followed by Q8W 2 mg IVT Afliber Xipu, until the 108th week.

Patients in the two treatment teams will complete the Q4W scheduled study visit for the entire study duration (112 weeks). Patients in the two treatment team groups will be administered a sham program at the time of the study visit without study treatment administration to maintain the shielding between the treatment team groups.

Figure 1 shows an overview of the research design a At the 20th and 24th week, the patient will undergo a disease activity assessment. Patients with anatomical or functional signs of disease activity at these time points will receive Q8W or Q12W administration, instead of Q16W administration, respectively. b The primary endpoint is based on the change from the baseline BCVA of the average at Week 40, Week 44, and Week 48 (as assessed on the ETDRS chart at a starting distance of 4 meters). c Starting from the 60th week (when all patients in team A are scheduled to receive fluxipilimab), patients in team A will be treated according to the PTI dosing schedule (between Q8W and Q16W). BCVA=best corrected visual acuity; ETDRS=early treatment of diabetic retinopathy; IVT=intravitreal; PTI=personalized treatment interval; Q8W=every 8 weeks; Q12W=every 12 weeks; Q16W=every 16 weeks; W=week .

Only one eye will be designated as the study eye. In the screening assessment, if both eyes are deemed eligible (according to the inclusion and exclusion criteria), the eye with the worse BCVA will be selected as the study eye (unless it is based on medical reasons, the researcher will look at the other eye To be more suitable for treatment under research).

There will be at least two researchers in each site to meet the sheltering needs of the research. At least one researcher will be designated as the assessing physician, who will obscure treatment assignments for each patient and they will assess the ocular assessment. At least one other researcher will be unmasked and will perform research treatments.

The study will consist of the following: a screening period of up to 28 days (-28 days to -1 day) and a treatment period of approximately 108 weeks, followed by the final study visit at week 112 (at least 28 days after the last study treatment administration) day).

20 weeks and 24 weeks of disease activity measurement criteria at 20 weeks and 24 weeks of active disease if any of the following guidelines: ● CST value as compared with the previous average of the two scheduled visits, increase CST> 50 µm (Week 20 assessment is for the 12th and 16th week visits, and the 24th week assessment is for the 16th and 20th visits); or ● and any of the previous two scheduled visits In one case, the CST increased by ≥ 75 μm compared to the lowest CST value recorded; or ● Due to the nAMD disease activity, the BCVA decreased by ≥ 5 letters compared with the average BCVA value of the two previous scheduled visits (e.g. Measured by personnel); or ● Due to nAMD disease activity, the BCVA decreased by ≥ 10 letters compared to the highest BCVA value recorded at any of the two previous scheduled visits (as determined by the researcher) ; Or ● due to nAMD activity, new macular hemorrhage occurs (as determined by the researcher).

Considering the additional factors Week 24: A group randomized to the team and obviously nAMD disease activity occurs during the first 24 weeks does not meet the above criteria, but the researchers believe would otherwise ensure that patients will at week 24 She received 6 mg of flucipilimab and will continue to receive repeated treatment every 12 weeks. Patients who are randomized to team A and meet the disease activity criteria at week 20 will maintain their Q8W dosing schedule and will not receive treatment at week 24. Patients randomized to team B will maintain their Q8W dosing schedule and will receive aflibercept at week 24.

The Personalized Treatment Interval (PTI) disease activity criterion starts at the 60th week. When all patients in Group A receive flucipilimab on a scheduled basis, the assessment will be based on the assessment conducted during the study drug administration visit Extend the study drug dosing interval for patients in group A. The study drug dosing interval decision (and the respective algorithms) of Team A during the PTI protocol phase is described in Table 2. Decisions will be made based on data from the patient's visit when receiving medication. When patients are not receiving treatment with fluxipilimab, they will undergo a sham procedure during the study visit. Table 2 Personalized treatment interval algorithm Dosing interval Guidelines The interval is extended by 4 weeks (to the maximum Q16W) ● Compared with the average value of the last two study drug administration visits, CST is stable ^a , and compared with the lowest measured value of the drug administration visit in the study, CST does not increase ≥ 50 μm, and ● compared with the last two Compared with the average value of the study drug administration visit, BCVA ^b did not decrease by ≥ 5 letters, and compared with the highest study drug administration visit measurement value, BCVA ^b did not decrease by ≥ 10 letters, and ● no new macular hemorrhage ^c If the interval is shortened ( to the minimum Q8W ), if one of the criteria is met, the interval will be shortened by 4 weeks. If two or more criteria are met or one criterion includes new macular hemorrhage, the interval will be shortened to an 8-week interval. ^c ● Compared with the average of the two most recent dosing visits, the CST increased by ≥ 50 µm, or compared with the lowest study dose visit measurement, the CST increased by ≥ 75 µm, or ● Compared with the two most recent study drug administrations Compared with the average value of the drug visit, BCVA ^{b is} reduced by ≥ 5 letters, or compared with the highest measured value of the drug administration visit in the study, BCVA ^{b is} reduced by ≥ 10 letters, or ● New macular hemorrhage ^c Interval maintenance When the criteria for extension or shortening have not been met BCVA = best corrected visual acuity; CST = macular center retinal thickness; IRF = intraretinal fluid; nAMD = neovascular age-related macular degeneration; Q8W = every 8 weeks; Q16W = every 16 weeks; SRF = subretinal fluid. ^a In the case where stability is defined as a change in CST of less than 30 µm. ^b The change in BCVA should be attributable to nAMD disease activity (as determined by researchers). ^c refers to macular hemorrhage caused by nAMD activity (as determined by researchers). ^d During the study period, patients who did not shorten the treatment interval from Q16W to Q8W by 8 weeks will return to the Q16W interval.

As outlined in Table 2 above, the algorithm used to make personalized drug treatment interval decisions is based on the relative change in CST and the absolute change in BCVA compared to the reference CST and BCVA; and additionally based on the assessment/discovery of new macular hemorrhage .

The algorithm can be implemented by a computing system or device. The computing system or device may include a web interface, mobile application, software program or any clinical decision support tool. For example, the patient's CST and BCVA scores can be uploaded to the web interface of the personalized dosing interval software tool. Using the uploaded CST and BVCA, the tool can automatically calculate and output the timing of the next dose. The tool can further provide dosing schedules or notifications, monitor and generate visualized results of dosing interval changes for a given patient, generate visualized results of dosing interval changes for patient groups, and aggregate the received CST and BCVA data to determine Trend, or a combination.

The dosing schedule or notification may include a calendar date showing the scheduled dosing visit and a calendar reminder to notify the clinician or the patient who is about to undergo the dosing visit. The visualization results of the change in dosing interval can include, for example, the schematic display in Table 2. In one case, the patient's dosing interval adjustment can be displayed in one color, and the patient's immediate previous dosing interval adjustment can be displayed in another color. For example, the patient can first extend their interval by 4 weeks, and then maintain their personalized treatment interval. The tool can generate a visualized result of the patient's personalized interval progression by displaying the "interval maintenance" area of the schematic diagram in green in Table 2 and the "interval extension by 4 weeks" in yellow. Green can reflect the patient's latest interval calculation and yellow can depict the result of the patient's immediate previous interval calculation. With this visualized result, the user of the tool can quickly determine that the patient's disease progression is improving, but it has not improved to the extent that the treatment interval can be extended more.

The tool can further aggregate patient and dosing schedule data and generate visualized results of aggregated data. Similar to the color coding example described previously, this type of data analysis can include the visualization of the administration changes of a single patient. Alternatively, the visualized results can show dosing adjustments for the patient group. For example, a visual result can show which patients have interval extension and which patients have interval shortening. This visualized result can be organized by various characteristics, such as patient age, previous treatment, disease condition, administered antibody, clinical trial group, and so on. The tool can also aggregate patient CST and BCVA data and generate visual results based on the data. Visualized results can show trends in data to facilitate or generate longitudinal analysis. These visual results can include reminders, curves, analytical workflow interfaces, or any graphical interface.

The tool can respond to or together with eye assessments and images to generate dosing schedule output or visualization results. In one embodiment, the tool can directly calculate the patient's CST or BVCA. Regarding CST, the tool can receive or directly capture eye images. The tool can further use image segmentation, image recognition or machine learning techniques to calculate CST based on eye images. Regarding BCVA, the tool can virtually manage eye assessments, prompt and collect patient user input via a user interface or via an eye tracking mechanism. Alternatively, the tool can receive, store, and track eye assessment data. In this way, the tool can track the disease progression of each patient and adjust the dosing schedule accordingly.

Embodiments of the present invention may include a method for providing a personalized medication schedule based on a personalized treatment interval (PTI) for treating patients suffering from nAMD, the method comprising: receiving patient data in a computing system, the patient data including the patient CST and best corrected visual acuity (BCVA); use the calculation system to extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; and obtain the PTI according to the dosing interval . When all the following criteria are met, the exemplary dosing interval is extended by 4 weeks (to a maximum of Q16W): i) The CST is stable compared to the average of the 2 most recent study drug dosing visits, where stability is defined as The change in CST is less than 30 µm and the CST does not increase ≥ 50 µm compared with the lowest measured value of the drug administration visit in the study. ii) Compared with the average of the two most recent study drug administration visits, the BCVA does not decrease ≥ 5 letters, and compared with the highest study drug administration visit measurement value, BCVA did not decrease ≥ 10 letters, iii) no new macular hemorrhage. The exemplary dosing interval is shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or if two or more of the following criteria are met, or one of the criteria includes new macular hemorrhage, Shorten the interval to 8 weeks: i) Compared with the average of the two most recent dosing visits, the CST increased by ≥50 µm, or compared with the lowest dosing visit measurement value, the CST increased by ≥75 µm, ii) Compared with the average of the last two dosing visits, BCVA decreased by ≥ 5 letters, or compared with the highest dosing visit measurement value, BCVA decreased by ≥ 10 letters, iii) new macular hemorrhage.

This method of providing a personalized dosing schedule based on a personalized treatment interval (PTI) for the treatment of patients suffering from nAMD may further include receiving updated patient data in a computing system; using the computing system, continuously based on the updated patient data Update or maintain the dosing interval; and generate visual results, user interfaces or notifications based on the updated or maintained dosing interval.

The embodiment of the present invention also includes the use of personalized drug delivery schedule (for the treatment of nAMD) based on a personalized treatment interval (PTI), where the computing system obtains the PTI by: receiving patient data, the patient data including the patient’s CST And best corrected visual acuity (BCVA); and based on the received patient data compared with the respective reference CST and BCVA, to extend, shorten or maintain the dosing interval. The exemplary dosing interval is extended by 4 weeks (to the maximum Q16W) if all the following criteria are met: i) Compared with the average of the last 2 study drug dosing visits, the CST is stable, where stability is defined as The change in CST is less than 30 µm and the CST does not increase ≥ 50 µm compared with the lowest measured value of the drug administration visit in the study. ii) Compared with the average of the two most recent study drug administration visits, the BCVA does not decrease ≥ 5 letters, and compared with the highest study drug administration visit measurement value, BCVA did not decrease ≥ 10 letters, iii) no new macular hemorrhage. The exemplary dosing interval is shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or if two or more of the following criteria are met, or one of the criteria includes new macular hemorrhage, Shorten the interval to 8 weeks: i) Compared with the average of the two most recent dosing visits, the CST increased by ≥ 50 µm, or compared with the lowest dosing visit measurement value, the CST increased by ≥ 75 µm; ii) Compared with the average of the last two dosing visits, the BCVA decreased by ≥ 5 letters, or compared with the highest dosing visit measurement value, the BCVA decreased by ≥ 10 letters; iii) new macular hemorrhage.

Ocular assessment given eye and the assessing comprises the following point at a specified time: ● by using three or Lighthouse from Precision Vision ^TM eye chart (Chart 2, and the improvement ETDRS R) measured BCVA. Provide VA manuals to researchers. Before performing any VA inspection, obtain VA inspector and VA inspection room certification. The study eye and treatment assignment will be shielded for the BCVA inspector and only refraction and BCVA assessments will be performed (for example, a vision specification booklet). The BCVA examiner also masks the BCVA letter scores of the patient's previous visit and only knows the patient's refraction data from the previous visit. BCVA inspectors are not allowed to perform any other tasks involving direct patient care. ● Low-brightness BCVA, as assessed on the ETDRS chart at the starting distance of the 4-meter low-brightness best-corrected vision test. There are the same requirements as the best corrected visual acuity described in Annex 4; however, the low-brightness best corrected visual acuity will be achieved by placing a 2.0 logarithmic neutral density filter (Kodak Wratten 2.0) above the optimal correction of the eye. Neutral density filter) and allow participants to read the normally illuminated early treatment diabetic retinopathy study chart to measure. ● IOP (Intraocular Pressure) measurement before treatment of both eyes (performed before eye expansion). ● Slit lamp examination (for grading anterior muscle and vitreous cells, see Foster CS, Kothari S, Anesi SD, etc., The Ocular and Uveitis Foundation preferred practice patterns of uveitis management. Surv Opthalmol 61 (2016) 1-17 ). ● Dilated binocular indirect high power ophthalmoscope. ● Refers to the calculation test, followed by the hand movement and light perception test (when needed) performed only by the unmasked treatment manager within 15 minutes after the study treatment of the study eye. ● During the research treatment visit, the post-treatment IOP measurement of the research eye can be performed within 30 (±15) minutes by qualified personnel with an unmasked role. If there are no safety issues after 30 (±15) minutes after the study treatment, the patient will be allowed to leave the clinic. If the IOP value is in the worries of the treatment manager, the patient will remain in the clinic and will be managed according to the clinical judgment of the treatment manager. When appropriate, adverse events will be recorded on the Electronic Case Report Form (eCRF) for adverse events.

The method used to measure the patient's IOP must remain constant throughout the study.

Eye imaging The Central Reading Center (CRC) will provide venues with manuals and training materials for the Central Reading Center designated to study eye images. Before obtaining any research images, the site personnel, test images, systems, and software (where applicable) will be authenticated and verified by the reading center as specified in the manual of the central reading center. All eye image results will be obtained by training site personnel at the research site and forwarded to the central reading center for independent analysis and/or storage.

After randomization, if the patient misses the study visit when the eye image is scheduled or when the image is not obtained during the scheduled visit (for example, due to broken equipment), the patient should be in the next scheduled visit. Obtain the image in time.

The eye image includes the following: ● Color fundus photography (CFP) of two eyes. Three-dimensional color fundus photos will be obtained from both eyes by trained personnel at the research site. Fundus photography will be performed at the interval specified in the active schedule. ● Fundus fluorescein angiography (FFA) of both eyes (performed after obtaining laboratory samples). Trainers certified by the Central Reading Center will perform fundus fluorescein angiography on both eyes at the research site. Fundus fluorescein angiography will be obtained at the intervals specified in the protocol. ● Spectral domain optical coherent tomography (SD-OCT) or scan source OCT (SS-OCT) images of both eyes. ● OCT-angiography (OCT-A) of two eyes selected as appropriate in places with agreed OCT-A capabilities. ● Circulating blood green angiography (ICGA) of the two eyes at the selected place with the agreed ICGA capability (performed after obtaining the laboratory sample). Circulating blood green angiography (ICGA) will be performed on both eyes at designated intervals by trained personnel certified by the Central Reading Center.

Results The main efficacy analysis included all randomized patients, among which the patients were grouped according to the treatment specified by the randomized group.

The main efficacy variable is the change in BCVA. The main power analysis will be performed using a mixed model (MMRM) such as a repeated measurement model.

Best corrected vision Measure BCVA as described. The main efficacy outcome measure is shown in the graph showing the main efficacy endpoint: the change in BCVA of the patient over time relative to the baseline. According to the research procedure described above, the bispecific anti-VEGF/ANG2 antibody RO6867461 ( Flusipilimab) (administered at 6.0 mg intravitreally as described in Team A using a personalized treatment interval) and, for example, Team B (Eylea® Q8W administration).

The change in central retinal thickness (CST) of the macula from baseline ( study eye ) The key secondary endpoint is the change from baseline CST (central retinal thickness of the macula). CST (and retinal thickness) was measured via optical coherence tomography (OCT). The results are shown in a graph in which the bispecific anti-VEGF/ANG2 containing the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 are displayed over time The CST change of antibody RO6867461 (fluxipilimab) (administered in 6.0 mg intravitreally as described in group A using a personalized treatment interval), according to the research procedure described above, compare this antibody to group B (Aflibercept for Q8W administration (Eylea®)) for comparison.

It can therefore show other results of eye assessment and imaging.

Example 2: Using personalized treatment intervals, the efficacy and durability of bispecific anti-VEGF/ANG2 in the treatment of patients with diabetic macular edema (DME) in the early stage II and 36 of patients with diabetic macular edema (DME) In the weekly study, some possibilities for longer durability (a longer period of time before retreatment) can be found in all participating patients. Three study groups were treated as follows: team group A: 0.3 mg lambizumab intravitreal (IVT); team group B: 1.5 mg RO6867461 (fluxipilimab) IVT; team group C: 6 mg RO6867461 (fluoro Sipilimumab) IVT.

The results of RO6867461 (fluxipilimab, VA2) that can reach retreatment for a longer time are shown in Figure 6. Figure 6 shows the time to retreatment in DME patients after the drug has been discontinued based on the disease activity assessed by the following two (after 20 weeks or once every 6 months) the most recent intravitreal (IVT) Time after administration): BCVA decrease ≥ 5 letters and CST increase ≥ 50 µm (= patients with events). The bispecific anti-VEGF/ANG2 antibody RO6867461 (fluxipilimab) (administered intravitreally at a dose of 6.0 mg or 1.5 mg) and Lambizumab (Lucentis®) (administered intravitreally at a dose of 0.3 mg) Compare.

A follow-up phase III study was started, which will now be evaluated as compared with aflibercept (Eylea®) monotherapy in patients with DME, administered to patients every 8 weeks (Q8W) and on a personalized treatment interval (PTI) schedule Efficacy, safety and pharmacokinetics of RO6867461 (fluxipilimab) at the time. The effect on visual function will be assessed by measuring the change in best corrected visual acuity (BCVA) (ie, the number of ETDRS letters) relative to the baseline. It will be evaluated by retinal imaging (spectral domain optical coherence tomography [SD-OCT], color fundus photography [CFP], fundus fluorescein angiography [FFA]) and other imaging modalities that evaluate both DME and DR results The effect on the anatomical structure of the retina. In addition, the safety, patient-reported results (PRO) and pharmacokinetics of RO6867461 will be assessed.

This study will evaluate the efficacy, safety, and pharmacokinetics of RO6867461 when compared with Eylea® monotherapy in patients with DME when Q8W is administered with the PTI regimen. The specific objectives and corresponding endpoints of the study are summarized in Table 3. Table 3 Goals and corresponding end points Main efficacy target Corresponding to the end ● To evaluate the efficacy of IVT injection of 6 mg fluxipilimab on BCVA results ● Change from baseline BCVA at 1 year (measured on the ETDRS chart at a starting distance of 4 meters) ^a Key secondary efficacy goals Corresponding to the end ● To assess the efficacy of fluxipilimab on the severity of DR results ● Proportion of patients with ≥ 2-step DRS improvement on ETDRS DRSS relative to baseline at week 52 Secondary efficacy goal Corresponding to the end ● To evaluate the efficacy of flucipilimab on additional BCVA results ● Change over time relative to baseline BCVA (as measured on the ETDRS chart at a starting distance of 4 meters) ● Increase over time relative to baseline BCVA by ≥ 15, ≥ 10, ≥ 5, or ≥ 0 letters Proportion of patients ● Proportion of patients who avoid BCVA loss of ≥ 15, ≥ 10, ≥ 5, or> 0 letters over time relative to baseline ● Patients who have increased by ≥ 15 letters or achieved BCVA of ≥ 84 letters over time The proportion of patients with a BCVA Snellen equivalent of 20/40 or better over time The proportion of patients with a BCVA Snellen equivalent of 20/200 or worse over time ● To evaluate the efficacy of fluxipilimab on additional DR results ● Proportion of patients with ≥ 2-step DRS improvement on ETDRS DRSS relative to baseline over time ● Proportion of patients with ≥ 3-step DRS improvement on ETDRS DRSS relative to baseline over time ● New PDR appearing over time Proportion of patients ● To assess the interval of fluxipilimab treatment in the PTI team ● The proportion of patients in the PTI team receiving Q4W, Q8W, Q12W, or Q16W treatment intervals at 1 and 2 years ● The treatment interval in the PTI team over time ^a 1 year is defined as the average of visits in the 48th week, 52nd week and 56th week. Table 3 Goals and corresponding endpoints (continued) Secondary efficacy goals ( continued ) Corresponding end point ( continued ) ● To use SD-OCT to evaluate the efficacy of fluxipilimab on the measurement of anatomical results ● Change from baseline CST at 1 year ^a ● Change from baseline CST over time ● No DME over time (for Spectralis SD-OCT, CST <325 μm or for Cirrus SD-OCT or Topcon SD- OCT, the proportion of patients with <315 μm) ● The proportion of patients with no intraretinal fluid over time ● The proportion of patients with no subretinal fluid over time ● The proportion of patients without intraretinal fluid and subretinal fluid over time Proportion of patients ● To use NEI VFQ-25 to evaluate the efficacy of fluxipilimab on patients’ reported vision-related functions and quality of life ● Changes over time relative to the baseline NEI VFQ-25 composite score Security goals Corresponding to the end ● To evaluate the ocular and systemic safety and tolerability of flucipilimab ● Incidence and severity of ocular adverse events ● Incidence and severity of non-ocular adverse events Exploratory efficacy goal Corresponding to the end ● To further evaluate the efficacy of fluxipilimab on additional DR results ● Proportion of patients with ≥ 2 steps or ≥ 3 steps worsening of DRS on ETDRS DRSS over time ● Proportion of patients who underwent vitrectomy or PRP over time during the study period ● using FFA and / or OCT-A matching Western fluoro evaluation results of the efficacy of mAb anatomical measurement of ^c ● Changes in ischemic non-perfusion (capillary loss) macular area and total retinal area ^b over time relative to baseline ● Changes in blood vessel leakage and total retinal area ^b over time relative to baseline macular ● Macula over time And the proportion of patients with vascular leakage in total retinal area ^b ● To use SD-OCT to further evaluate the efficacy of flusipilimab on the measurement of anatomical results ● Change in sensory nerve CST over time relative to baseline ● Change in total macular volume over time relative to baseline ^a 1 year is defined as the average of visits in the 48th week, 52nd week and 56th week. ^b Define the total retinal area as 7 modified fields or 4 wide fields of view or ETDRS 7 field of view occlusion on the ultra-wide field (UWF; Optos ^{®) images of all patients under study and defined as the entire UWF image, including} Peripheral area of the subgroup of patients with Optos FFA. ^c In the subgroup of patients with OCT-A. Table 3 Goals and corresponding endpoints (continued) Exploratory efficacy goals ( continued ) Corresponding end point ( continued ) ● To use NEI VFQ-25 to further evaluate the efficacy of fluxipilimab on patients’ reported vision-related functions and quality of life ● at 1 year ^a baseline NEI VFQ-25 near activity, from the activity and the driving subscales changes ● ^a when NEI VFQ-25 composite score aspect baseline patients ≥ 4 Spot in the 1 year ratio Pharmacokinetic goals Corresponding to the end ● To characterize the systemic pharmacokinetics of flucipilimab ● Fluxipilimab plasma concentration over time Immunogenic target Corresponding to the end ● To assess the immune response to flucipilimab ● Relative to the presence of ADA at the baseline, the presence of ADA during the study period ● To evaluate the potential effects of ADA ● Relationship between ADA status and efficacy, safety or PK endpoint Exploratory pharmacokinetics, pharmacodynamics and biomarker targets Corresponding to the end ● In order to identify the biomarkers that predict the response to fluxipilimab are related to the progression of more serious disease conditions and the sensitivity to the occurrence of adverse events, it can provide evidence of fluxipilimab activity or increase disease biology Knowledge and understanding ● The concentration of biomarkers of angiogenesis at baseline and over time and the inflammation of ocular fluid (if any) and their correlation with PK and/or primary and secondary endpoints at baseline and over time ● Efficacy and safety The relationship between sex, PK, immunogenicity or other biomarker endpoints and gene polymorphisms at loci (including but not limited to VEGFA and ANGPT2) Baseline anatomical measurements and BCVA or other endpoints over time ( For example, study the relationship between changes in the frequency of drug administration ● The relationship between anatomical measurements and visual acuity ^a 1 year is defined as the average of visits in the 48th week, 52nd week and 56th week. Table 3 Goals and corresponding endpoints (continued) Exploratory pharmacokinetics, pharmacodynamics and biomarker targets ( continued ) Corresponding end point ( continued ) ● To assess the potential relationship between selected covariates and exposure to fluxipilimab ● The relationship between the selected covariates and the concentration of fluxipilimab in plasma or aqueous humor (as appropriate) or PK parameters ● To characterize the pharmacokinetics of fluxipilimab's ocular fluid (as the case exists) and vitreous (as the case exists) ● Concentrations of fluxipilimab in ocular fluid (as the case exists) and vitreous (as the case exists) over time ● To evaluate the drug concentration (exposure)-effect relationship without VEGF-A and without Ang-2 ● The relationship between the pharmacokinetics of fluxipilimab and the concentration of VEGF-A and Ang-2 without VEGF-A and Ang-2 in ocular fluid (as the case exists), plasma and/or vitreous (as the case exists) over time ● To explore the concentration-effect relationship of vision and other endpoints (for example, anatomical markers) ● Changes in the pharmacokinetics of fluxipilimab and BCVA or other endpoints (for example, anatomical markers) over time Abbreviations in the table ADA=anti-drug antibody; Ang-2=angiogenin-2; ANGPT2=angiogenin-2 (gene); BCVA=best corrected visual acuity; CST=macular center retinal thickness; DR=diabetic retina Disease; DRS=severity of diabetic retinopathy; DRSS=severity of diabetic retinopathy; ETDRS=early treatment of diabetic retinopathy; FFA=fundus fluorescein angiography; IVT=intravitreal; NEI VFQ-25 =National Eye Society 25-item Visual Function Questionnaire; OCT-A=Optical Coordination Tomography-Angiography; PDR=Proliferative Diabetic Retinopathy; PK=Pharmacokinetics; PRP=Pan Retinal Photocoagulation; PTI=Personalized Treatment Interval ; Q4W=every 4 weeks; Q8W=every 8 weeks; Q12W=every 12 weeks; Q16W=every 16 weeks; SD-OCT=spectral domain optical coherent tomography; VEGFA=vascular endothelial growth factor-A (gene).

Patients suffering from DME (for example, related to central diabetic macular edema (CI-DME)) are treated with a bispecific antibody that binds to human VEGF and human ANG2, the bispecific antibody comprising SEQ ID NO: 17, SEQ ID NO : 18. The amino acid sequences of SEQ ID NO: 19 and SEQ ID NO: 20 (this antibody VEGFang2-0016 and its production are also described in detail in WO2014/009465 incorporated by reference). The name of this bispecific anti-VEGF/ANG2 antibody herein is RO6867461 or RG7716 or VEGFang2-0016 or flucipilimab. In the treatment, for example, aflibercept will be used as an active comparison agent. Patients include patients who have not been treated with anti-VEGF therapy (not previously treated with anti-VEGF therapy such as Abbaxifen/or Lambizumab and/or other anti-VEGF therapies) and a group of patients who have previously been treated with anti-VEGF therapy Patients treated. Use a sterile, colorless to light brown, preservative-free vial of RO6867461 (fluxipilimab) for intravitreal (IVT) administration at a dose of 6 mg. RO6867461 (fluxipilimab) will be administered at a concentration of approximately 120 mg/ml.

During the global registration phase of the study, approximately 900 patients will be randomized at a ratio of 1:1:1 to one of the three treatment team groups at approximately 240 research sites around the world (see Figure 2). The study will randomize patients with DME whose study eyes have not been treated with anti-VEGF therapy and patients whose study eyes have been previously treated with anti-VEGF therapy. The limitation is that the last treatment is on the first day visit (first visit). At least 3 months before study treatment). The site researchers will be retinal experts.

The research treatment team will be as follows (see also Figure 2): Team A (Q8W administration): Patients randomized to team A will receive Q4W 6-mg IVT RO6867461 (fluxipilimab) injection until week 20, followed by Q8W 6-mg IVT RO6867461 (fluxipil Monoclonal antibody) was injected to the 96th week, followed by the final study visit at the 100th week. Team B (Personalized Treatment Interval): Patients randomized to Team B will receive Q4W 6-mg IVT RO6867461 (fluxipilimab) injection until at least the 12th week, followed by 6-mg IVT RO6867461 (fluoro The PTI administration of sipilimab injection (see PTI administration guidelines below) until the 96th week, followed by the final study visit at the 100th week. Team group C (comparative agent team group) (Q8W administration): Patients randomized to team group C will receive Q4W 2-mg IVT aflibercept injection until week 16, followed by Q8W 2-mg IVT Aflibercept was injected until the 96th week, followed by the final study visit at the 100th week.

Patients in all three treatment team groups will complete the Q4W scheduled study visit for the entire study duration (100 weeks). A sham procedure will be administered to patients in all three treatment team groups at the applicable visit to maintain shielding between treatment team groups (see Figure 2 -Study Treatment Plan).

Only one eye will be designated as the study eye. In the screening assessment, if both eyes are deemed eligible, the eye with the worse BCVA will be selected as the study eye unless the researcher regards the other eye as more suitable for the treatment under study.

There will be at least two researchers in each site to meet the sheltering needs of the research. At least one researcher will be designated as the assessing physician, who will obscure treatment assignments for each patient and they will assess the ocular assessment. At least one other researcher will be unmasked and will perform the study treatment (for additional masking details, see section 4.2.2).

Decision therapeutic dosing interval PTI team schedule set for the individual treatment interval (PTI) group team (team group B), of the patient described in this section. The study drug administration visit was regarded as the visit when the patient was designated to receive fluxipilimab (RO6867461).

Study drug dosing interval determination Patients randomized to the PTI team (team B) will be treated with flucipilimab at a Q4W dosing interval until the patient’s 12th week or later visit CST meets the predetermined reference CST threshold (for Spectralis SD- OCT, CST <325 µm, or for Cirrus SD-OCT or Topcon SD-OCT, <315 µm). The reference CST is used for interval decision during study drug dosing visits.

After determining the patient's initial reference CST, the study drug dosing interval will be increased by 4 weeks to the initial Q8W dosing interval. From this moment on, the study drug dosing interval will be extended, shortened, or maintained based on the assessment made during the study drug dosing visit.

Figure 3 outlines the algorithm used for interval decision, which is based on the relative changes of CST and BCVA compared to the reference CST and the reference BCVA. In Figure 3, * and ** mean the following: * Reference macular central retinal thickness (CST): CST value when the initial CST threshold is met. The reference CST was adjusted when the CST was reduced by> 10% from the previous reference CST of two consecutive study drug administration visits, and the value obtained was within 30 μm. The CST value obtained during subsequent visits will serve as the new reference CST, starting immediately from that visit. ** Reference best corrected visual acuity (BCVA): the average of the three best BCVA scores obtained at any previous dosing visit.

All comparisons are made regarding reference CST* and reference BCVA**. The drug administration interval was determined based on the CST and BCVA data obtained from the drug administration visit.

In the following cases, the interval is extended by 4 weeks: ● The CST value increases or decreases by ≤ 10%, and there is no related BCVA decrease ≥ 10 letters

The interval is maintained under the following conditions : ● CST decrease> 10%, or ● CST value increase or decrease ≤ 10%, with associated BCVA decrease ≥ 10 letters, or ● CST value increase> 10% and ≤ 20%, and No related BCVA decrease ≥ 5 letters;

In the following cases, the interval is shortened by 4 weeks : ● CST value increase> 10% and ≤ 20%, with associated BCVA decrease ≥ 5 to <10 letters, or ● CST value increase> 20% without related BCVA decrease ≥ 10 letters

In the following cases, the interval is shortened by 8 weeks : ● The CST value increases> 10%, and the associated BCVA decreases ≥ 10 letters * Reference macular central retinal thickness (CST): CST value when the initial CST threshold is met. The reference CST was adjusted when the CST was reduced by> 10% from the previous reference CST of two consecutive study drug administration visits, and the value obtained was within 30 μm. The CST value obtained during subsequent visits will serve as the new reference CST, starting immediately from that visit. ** Reference best corrected visual acuity (BCVA): the average of the three best BCVA scores obtained at any previous dosing visit.

The interval of personalized medicine administration can be adjusted in 4-week increments, to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. The algorithm for personalized medication interval decision is based on the relative change of CST and the absolute change of BCVA compared with the reference CST and BCVA, respectively.

The algorithm can be implemented by a computing system or device. The computing system or device may include a web interface, mobile application, software program or any clinical decision support tool. For example, the patient's CST and BCVA scores can be uploaded to the web interface of the personalized dosing interval software tool. Using the uploaded CST and BVCA, the tool can automatically calculate and output the timing of the next dose. The tool can further provide dosing schedules or notifications, monitor and generate visualized results of dosing interval changes for a given patient, generate visualized results of dosing interval changes for patient groups, and aggregate the received CST and BCVA data to determine Trend, or a combination.

The dosing schedule or notification may include a calendar date showing the scheduled dosing visit and a calendar reminder to notify the clinician or the patient who is about to undergo the dosing visit. The visualized results of the change in the dosing interval may include, for example, the schematic display in FIG. 3. In one case, the patient's dosing interval adjustment can be displayed in one color, and the patient's immediate previous dosing interval adjustment can be displayed in another color. For example, the patient can first extend their interval by 4 weeks, and then maintain their personalized treatment interval. The tool can generate a visualized result of the patient's personalized interval progression by displaying the "interval maintenance" area of the schematic diagram in green in FIG. 3 and the "interval extension by 4 weeks" in yellow. Green can reflect the patient's latest interval calculation and yellow can depict the result of the patient's immediate previous interval calculation. With this visualized result, the user of the tool can quickly determine that the patient's disease progression is improving, but it has not improved to the extent that the treatment interval can be extended more.

The tool can further aggregate patient and dosing schedule data and generate visualized results of aggregated data. Similar to the color coding example described previously, this type of data analysis can include the visualization of the administration changes of a single patient. Alternatively, the visualized results can show dosing adjustments for the patient group. For example, a visual result can show which patients have interval extension and which patients have interval shortening. This visualized result can be organized by various characteristics, such as patient age, previous treatment, disease condition, administered antibody, clinical trial group, and so on. The tool can also aggregate patient CST and BCVA data and generate visual results based on the data. Visualized results can show trends in data to facilitate or generate longitudinal analysis. These visual results can include reminders, curves, analytical workflow interfaces, or any graphical interface.

The tool can respond to or together with eye assessments and images to generate dosing schedule output or visualization results. In one embodiment, the tool can directly calculate the patient's CST or BVCA. Regarding CST, the tool can receive or directly capture eye images. The tool can further use image segmentation, image recognition or machine learning techniques to calculate CST based on eye images. Regarding BCVA, the tool can virtually manage eye assessments, prompt and collect patient user input via a user interface or via an eye tracking mechanism. Alternatively, the tool can receive, store, and track eye assessment data. In this way, the tool can track the disease progression of each patient and adjust the dosing schedule accordingly.

Embodiments of the present invention may include a method for providing a personalized dosing schedule based on a personalized treatment interval (PTI) for treating a patient suffering from DME, the method comprising: receiving patient data in a computing system, the patient data including the patient CST and best corrected visual acuity (BCVA); use the calculation system to extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; and obtain the PTI according to the dosing interval . In the case of an increase or decrease in CST value of ≤ 10%, and no related BCVA decrease of ≥ 10 letters, the exemplary dosing interval is extended by 4 weeks. The exemplary dosing interval will be maintained in the following cases: CST decrease> 10%, CST value increase or decrease ≤ 10%, with associated BCVA decrease ≥ 10 letters, or CST value increase> 10% and ≤ 20%, And there is no related BCVA decrease ≥ 5 letters. In the following cases, the exemplary dosing interval is shortened by 4 weeks: CST value increases> 10% and ≤ 20%, with associated BCVA decrease ≥ 5 to <10 letters; or CST value increases> 20% without correlation The BCVA decreases by ≥ 10 letters. In the case of a CST value increase of> 10%, with a related BCVA decrease of ≥ 10 letters, the exemplary dosing interval is shortened by 8 weeks.

This method of providing a personalized dosing schedule based on a personalized treatment interval (PTI) to treat patients suffering from DME may further include receiving updated patient information in a computing system; using the computing system to continuously update or based on the updated patient information Maintain the dosing interval; and generate visual results, user interfaces, or notifications based on the updated or maintained dosing interval.

The embodiment of the present invention also includes the use of personalized dosing schedule (for the treatment of DME) according to the personalized treatment interval (PTI), where the computing system obtains the PTI by: receiving the patient’s CST and the best corrected vision ( BCVA) patient data; and based on the received patient data compared with the respective reference CST and BCVA, to extend, shorten or maintain the dosing interval. In the case of an increase or decrease in CST value of ≤ 10%, and no related BCVA decrease of ≥ 10 letters, the exemplary dosing interval is extended by 4 weeks. The exemplary dosing interval will be maintained under the following conditions: CST decrease> 10%, or CST value increase or decrease ≤ 10%, with associated BCVA decrease ≥ 10 letters, or CST value increase> 10% and ≤ 20% , And there is no related BCVA decrease ≥ 5 letters. In the following cases, the exemplary dosing interval is shortened by 4 weeks:-CST value increases> 10% and ≤ 20%, with associated BCVA decrease ≥ 5 to <10 letters; or CST value increases> 20%, and No related BCVA decrease ≥ 10 letters. In the case of a CST value increase of> 10%, with a related BCVA decrease of ≥ 10 letters, the exemplary dosing interval is shortened by 8 weeks. Similar to team A and team C, when the patient is not receiving treatment with fluxipilimab, patients randomized to the PTI team (team B) will undergo a sham procedure during the study visit.

Ocular assessment given eye and the evaluation includes the following depending on the activity schedule of both eyes performed assessed at the indicated times: • in the evaluation of the refractive and BCVA ETDRS chart starting at 4 meters distance. Measure BCVA by using three Precision Vision ^TM or Lighthouse distance acuity charts (modified ETDRS charts 1, 2 and R). Provide VA manuals to researchers. Before performing any VA inspection, obtain VA inspector and VA inspection room certification. The study eye and treatment assignment will be shielded for the BCVA inspector and only refraction and BCVA assessments will be performed (for example, a vision specification booklet). The BCVA examiner also masks the BCVA letter scores of the patient's previous visit and only knows the patient's refraction data from the previous visit. BCVA inspectors are not allowed to perform any other tasks involving direct patient care. • IOP (Intraocular Pressure) measurement before treatment of both eyes (performed before eye expansion). • Slit lamp examination (for grading anterior muscle and vitreous cells, see Foster CS, Kothari S, Anesi SD, etc., The Ocular and Uveitis Foundation preferred practice patterns of uveitis management. Surv Opthalmol 61 (2016) 1-17 ). • Dilated binocular indirect high power ophthalmoscope. • Means test, followed by hand movement and light perception test (when needed) performed only by the manager of the unmasked treatment within about 15 minutes after the study treatment of the study eye. • During the study treatment visit, the post-treatment IOP measurement of the study eye was performed only at 30 (±15) minutes by qualified personnel with an unmasked role. If there are no safety issues after 30 (±15) minutes after the study treatment, the patient will be allowed to leave the clinic. If the IOP value is in the concern of the treatment manager, the patient will remain in the clinic and will be managed according to the physician's clinical judgment. When appropriate, adverse events will be recorded on the Electronic Case Report Form (eCRF) for adverse events. The method used to measure the patient's IOP must remain constant throughout the study.

Eye imaging The Central Reading Center (CRC) will provide venues with CRC manuals and training materials for the designated study of eye images. Before obtaining any research images, the CRC as specified in the CRC manual will be used to authenticate and verify site personnel, test images, systems and software (where applicable). All eye image results will be obtained by training site personnel at the research site and forwarded to CRC for independent analysis and/or storage.

After randomization, if the patient misses the study visit when the eye CFP and FFA images are scheduled or when no images are obtained during the scheduled visit (for example, due to broken equipment), the patient should be in the next time the patient participates. Obtain images during scheduled visits.

Eye imaging includes the following : ● Compulsory color fundus photography (CFP) for both eyes (7 or 4 wide fields; one of these methods is performed for patients who always participate in the entire trial). Three-dimensional color fundus photos will be obtained from both eyes by trained personnel at the research site. Fundus photography will be performed at the interval specified in the active schedule. ● Ultra-wide-field (UWF; Optos ^® ) CFP (UWF; Optos ®) CFP selected according to the situation for both eyes (in a place with UWF CFP capability and agree to obtain these images except for the required CFP images) ● Trainers will be used to study Perform fundus fluorescein angiography (FFA) for both eyes at the venue (always participate in the test, if the venue is capable, the best method is UWF (Optos) FFA; without UWF (Optos) The FFA site uses the same method to capture 7 or 4 wide areas (if feasible, perform after obtaining blood samples). UWF (Optos) is the better method for fundus fluorescein angiography (FFA) capture. Optos is not available Equipment and certificate research sites must use 7 or 4 wide-field FFA captures. ● Spectral domain optical coherence tomography (SD-OCT) or scan source OCT (SS-OCT) images of both eyes. ● OCT-A capability OCT-angiography (OCT-A), which is optional, on both eyes at the site and agreed by the site to obtain these images.

Results The main efficacy analysis included all randomized patients, among which the patients were grouped according to the treatment specified by the randomized group.

The main efficacy variable is the change in BCVA as described herein. The main power analysis will be performed using a mixed model (MMRM) such as a repeated measurement model.

Best corrected visual acuity The BCVA is measured as described. The main efficacy outcome measure is shown in the graph showing the main efficacy endpoint: the change in BCVA of the patient over time relative to the baseline. According to the research procedure described above, the bispecific anti-VEGF/ANG2 antibody RO6867461 ( Fluxipilimab) (using a personalized treatment interval as described in team group B with 6.0 mg intravitreal administration) and, for example, team group A (fluxipilimab administered at Q8W) and/or team group C (Aflibercept (Eylea®) Q8W administration) for comparison.

The change in central retinal thickness (CST) of the macula from baseline ( study eye ) The key secondary endpoint is the change from baseline CST (central retinal thickness of the macula). CST (and retinal thickness) was measured via optical coherence tomography (OCT). The results are shown in a graph, which shows the bispecific anti-VEGF/s containing the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 over time. The CST change of the ANG2 antibody RO6867461 (fluxipilimab) (administered in 6.0 mg intravitreally as described in group B using a personalized treatment interval), according to the research procedure described above, compare this antibody to the group A (fluxipilimab administered Q8W) and/or group C (Aflibercept (Eylea®) administered Q8W) were compared.

It can therefore show other results of eye assessment and imaging.

Example 3: Using personalized treatment intervals, suffering from macular edema secondary to retinal vein occlusion (RVO) (secondary to central retinal vein occlusion (CRVO), secondary to semiretinal vein occlusion (HRVO), or secondary to branch veins The efficacy and durability of bispecific anti-VEGF/ANG2 therapy for patients with obstructive macular edema (BRVO). Non-clinical studies have shown that Ang-2 and VEGF act synergistically to regulate vascular structure and increase the permeability of retinal endothelial cells in vitro . Compared with the molar equivalent of anti-VEGF (lambizumab) or anti-Ang-2 alone, the bispecific monoclonal antibody flucipilizumab inhibits both Ang-2 and VEGF in non-human primates. The laser-induced CNV model caused a greater reduction in the leakage and severity of choroidal neovascular (CNV) lesions. Early experiments using a mouse model of spontaneous CNV showed that in terms of vascular growth, leakage, edema, leukocyte infiltration, and loss of light-receiving organs, the dual inhibition of Ang-2 and VEGF always outperformed any single target alone. Drug therapy inhibition (Regula JT, Lundh von Leithner P, Foxton R, et al., EMBO Mol Med 2016; 8: 1265-1288).

In addition, it was shown that the aqueous and vitreous concentrations of both Ang-2 and VEGF are up-regulated in patients with neovascular age-related macular degeneration (nAMD), DR and RVO (Tong JP, Chan WM, Liu DT et al., Am J Ophthalmol 2006;141:456-462; Penn JS, Madan A, Caldwell RB et al., Prog Retin Eye Res 2008;27:331-371.; Kinnunen K, Puustjärvi T, Teräsvirta M et al., Br J Ophthalmol 2009 ;93:1109-1115;Tuuminen R, Loukovaara S. Eye (Lond) 2014;28:1095-1099;Regula JT, Lundh von Leithner P, Foxton R et al., EMBO Mol Med 2016;8:1265-1288;Ng DS, Yip YW, Bakthavatsalam M et al., Sci Rep 2017;7:45081). Therefore, compared with anti-VEGF therapy alone, the simultaneous neutralization of the two targets Ang-2 and VEGF can further standardize the pathological ocular vascular structure. The data from the complete Phase II study of DME and nAMD (see below) also supports the hypothesis that targeting Ang-2 in diseases that affect retinal vascular structure has the potential to extend efficacy durability beyond the potential of anti-VEGF therapy alone.

Has been in two phase I studies (BP28936 in nAMD and JP39844 in nAMD and DME) and three phase II studies (BP29647 [AVENUE] and CR39521 [STAIRWAY] for nAMD and BP30099 [BOULEVARD] for DME) In the study of fluxipilimab for the treatment of nAMD and DME. Four global phase III studies are in progress: GR40349 (YOSEMITE) and GR40398 (RHINE) of DME and GR40306 (TENAYA) and GR40844 (LUCERNE) of nAMD.

Based on the mechanism of action of fluxipilimab, data from non-clinical and clinical trials, and the pathophysiology of macular edema caused by RVO, it is hypothesized that fluxipilimab can cause pathology compared with anti-VEGF monotherapy Stabilize the ocular vascular structure and improve the visual and anatomical results of RVO.

Macular edema secondary to RVO/RVO is the highest among retinal vascular diseases (Aiello LP, Avery RL, Arrigg PG et al., N Engl J Med 1994; 331:1480-1487; Regula JT, Lundh von Leithner P, Foxton R et al., EMBO Mol Med 2016;8:1265-1288). The efficacy of Ang-2 and VEGF inhibition in non-clinical models of angiogenesis and inflammation (Regula JT, Lundh von Leithner P, Foxton R et al., EMBO Mol Med 2016; 8: 1265-1288) and from patients with nAMD and DME The data from the Phase I and Phase II flucipilimab studies of the patients provide evidence of the effectiveness of pathological pathways, which are caused by all three retinal vascular diseases nAMD, DME/DR, and macular edema due to RVO Shared (Phase I study: BP28936 in nAMD; Phase II study: AVENUE in nAMD, STAIRWAY in nAMD and BOULEVARD in DME).

Due to the similar pathophysiology between DME and macular edema due to RVO, data from the Phase II BOULEVARD study are reported here. Although the triggers of macular edema in diabetic and RVO patients are different, the downstream pathophysiology of hypoxia-driven macular edema and subsequent vision loss is similar and consists of the same pro-angiogenesis, pro-inflammatory, vascular instability and vascular permeability factors (Including Ang-2, VEGF and Interleukin-6 (IL-6)) driven. The results of RO6867461 (fluxipilimab, VA2) that can reach retreatment for a longer time are shown in Figure 6. Figure 6 shows the time to retreatment in DME patients after the drug has been discontinued based on the disease activity assessed by the following two (after 20 weeks or once every 6 months) the most recent intravitreal (IVT) Time after administration): BCVA decrease ≥ 5 letters and CST increase ≥ 50 µm (= patients with events). The bispecific anti-VEGF/ANG2 antibody RO6867461 (fluxipilimab) (administered intravitreally at a dose of 6.0 mg or 1.5 mg) and Lambizumab (Lucentis®) (administered intravitreally at a dose of 0.3 mg) Compare.

The BOULEVARD study provides basic evidence of the positive benefit/risk profile of 6-mg IVT fluxipilimab injection for patients with DME and supports the further evaluation of fluxipilimab in the Phase III DME study. The study met its primary efficacy endpoint, confirming the average change from baseline BCVA at week 24 in patients treated with 6 mg fluxipilizumab and not treated with anti-VEGF compared with 0.3 mg lambizumab The statistically significant improvement.

The results of the discontinuation of the treatment study observation period provide evidence of the prolonged duration of efficacy of fluxipilimab compared to anti-VEGF monotherapy.

The assessment of the time to disease reactivation after the last dose is as high as 16 weeks shows that fluxipilizumab is better than lambilizumab in the improvement of the duration of efficacy, such as by improving the duration of efficacy in a dose-dependent manner. Measured by the time it takes to lose ≥ 5 letters of the Early Treatment Diabetic Retinopathy Study (ETDRS) and the central retinal thickness (CST) of the macula ≥ 50 µm in the patient population due to DME. This improvement in the duration of efficacy of fluxipilizumab over lambilizumab was also found in the previous treatment group and the total patient group. Based on all of these non-clinical and clinical signs, treatment with fluxipilimab can produce improved efficacy that is superior to the standard of anti-VEGF care in patients with macular edema due to RVO. In addition, this study adapts the study to individual needs for less frequent treatment dosing schedules (at most every 16 weeks), which can provide a schedule with more frequent anti-VEGF monotherapy (e.g., every 4 to 8 weeks). ) Comparable BCVA results. In short, these will represent important and meaningful advances relative to currently available therapies.

The research design began to evaluate flucipilimab (a bispecific antibody that binds to human VEGF and human ANG2, which includes the amines of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20) Base acid sequence (VEGFang2-0016 WO2014/009465, incorporated by reference, the name of this bispecific anti-VEGF/ANG2 antibody herein is RO6867461 or RG7716 or VEGFang2-0016 or fluxipilimab)) Phase III, multi-center, randomized, double-blind, active comparator controlled, parallel group study of efficacy, safety and pharmacokinetics, which is in patients with secondary CRVO or HRVO or BRVO/because of CRVO or HRVO or BRVO In patients with macular edema, IVT injections were administered at 4-week intervals until the 24th week, followed by a double-blind study period with no active control to evaluate the administration of fluxipilimab according to the PTI dosing schedule .

Overview of Study Design This study consists of two parts: Part 1 (Day 1 to Week 24) will compare flucipilimab Q4W with aflibercept (active comparator) Q4W; Part 2 (Week 24 to Week 72) Weeks) will be administered with flucipilimab based on the PTI dosing criteria assessment to cover the treatment interval Q4W to Q16W.

In Part 1 (Q4W administration), during the global registration phase of the study, approximately 680 patients will be randomly assigned to one of the two treatment team groups at a 1:1 ratio, where treatment is defined as follows: -Team A (n=340): Patients randomly assigned to team A will receive flucipilimab 6 mg IVT Q4W (6 injections) from day 1 to week 20. -Team group B (comparative agent team group, n=340): Patients randomly assigned to team group B will receive aflibercept 2 mg IVT Q4W (6 injections) from day 1 to week 20.

In Part 2 (PTI regimen), patients in both groups A and B will receive fluxipilimab 6 mg IVT according to the PTI dosing regimen from week 24 to week 68.

All patients will complete the Q4W scheduled study visit for the entire duration of the study (72 weeks). In order to keep the fluxipilimab treatment interval shielded from the 24th week to the 68th week, a sham program will be administered during the study visit where no fluxipilimab treatment (according to the PTI dosing schedule) is administered.

Figure 7 shows an overview of the research design.

Only one eye will be designated as the study eye. In the screening assessment, if both eyes are deemed eligible, the eye with the worse BCVA will be selected as the study eye unless the researcher regards the other eye as more suitable for the treatment under study. There will be at least two researchers in each site to meet the sheltering needs of the research. At least one researcher will be designated as the assessing physician, who will obscure treatment assignments for each patient and they will assess the ocular assessment. At least one other researcher will be unmasked and will perform research treatments.

The study will consist of the following: a screening period of up to 28 days (-28 days to -1 day) and a treatment period of approximately 68 weeks, followed by the final study visit at week 72.

Goals and destinations This study will evaluate the primary endpoint until the 24th week. Compared with aflibercept, fluxipilimab is more effective in patients with macular edema secondary to CRVO or HRVO or BRVO. Efficacy, safety and pharmacokinetics. The efficacy, safety and pharmacokinetics of fluxipilimab administered according to the PTI dosing regimen (ie Q4W to Q16W) will be evaluated during the study period from week 24 to week 72. The specific objectives and corresponding endpoints of the study are summarized below. In this protocol, "study drug" refers to fluxipilimab or aflibercept, and "study treatment" refers to fluxipilimab, aflibercept or sham procedure.

Efficacy goal Regarding the evaluation of the efficacy endpoint, the BCVA will be evaluated on the ETDRS eye chart at a starting test distance of 4 meters.

Main efficacy goals The main efficacy goals of this study are based on the following endpoints to evaluate the efficacy of fluxipilimab 6 mg IVT Q4W compared to aflibercept 2 mg IVT Q4W:-Change from baseline BCVA at week 24

Secondary efficacy goal Part of this research 1 ( That is to the first twenty four week ) Of The secondary efficacy target is based on the following endpoint assessment compared to aflibercept , Efficacy of flucipilimab : -The change from the baseline BCVA at the specified time point up to the 24th week -In thetwenty four week Proportion of patients whose BCVA increased by ≥ 15 letters from baseline at time -Proportion of patients whose BCVA increased by ≥ 15, ≥ 10, ≥ 5 or ＞ 0 letters from the baseline at the designated time point up to the 24th week -Proportion of patients who avoided BCVA loss of ≥ 15, ≥ 10, ≥ 5, or ≥ 0 letters relative to the baseline at the designated time point up to the 24th week -Proportion of patients with BCVA ≥ 84 letters (20/20 Snellen equivalent) at the designated time point up to the 24th week -Proportion of patients with a BCVA Snellen equivalent value of 20/40 or better at the specified time point up to the 24th week -The proportion of patients with a BCVA Snellen equivalent of 20/200 or worse at the designated time point up to the 24th week -The change in CST from the baseline at the specified time point up to the 24th week -The change in the composite score of the 25-item Visual Function Questionnaire (NEI VFQ-25) from the baseline National Ophthalmology Society at the designated time point up to the 24th week

Part of this research 2 ( That is, the first twenty four week To the first 72 week ) Of The secondary efficacy target is based on the following endpoints to assess the basis PTI Efficacy of fluxipilimab administered by dosing regimen : -The change from the baseline BCVA at the specified time point from the 24th week to the 72nd week -Proportion of patients whose BCVA increased by ≥ 15 letters from baseline at week 24 -Proportion of patients whose BCVA increased by ≥ 15, ≥ 10, ≥ 5 or ＞ 0 letters from the baseline at the designated time point from week 24 to week 72 -Proportion of patients who avoided BCVA loss ≥ 15, ≥ 10, ≥ 5, or ＞ 0 letters relative to baseline at the designated time point from week 24 to week 72 -Proportion of patients with BCVA ≥ 84 letters (20/20 Snellen equivalent) at the designated time point from week 24 to week 72 -Proportion of patients with a BCVA Snellen equivalent value of 20/40 or better at the designated time point from week 24 to week 72 -Proportion of patients with a BCVA Snellen equivalent value of 20/200 or worse at the specified time point from week 24 to week 72 -The change of BCVA at the specified time point from the 24th week to the 72nd week -Proportion of patients who avoid BCVA loss of ≥ 15, ≥ 10, ≥ 5 or ＞ 0 letters from week 24 to week 72 -Proportion of patients receiving Q4W, every 8 weeks (Q8W), every 12 weeks (Q12W) or Q16W treatment interval at 72 weeks -The number of study drug injections received from week 24 to week 72 -The change from the baseline CST at the specified time point from the 24th week to the 72nd week -The change from the baseline NEI VFQ-25 composite score at the specified time point from the 24th week to the 72nd week

Exploratory efficacy goal The exploratory efficacy goal of this study is to evaluate the efficacy of fluxipilimab based on the following endpoints:-Fundus fluorescein angiography (FFA) and optical coherent tomography over time (at designated time points) Proportion of patients without retinal ischemia on angiography (OCT-A) (as the case may be)-change over time in FFA and OCT-A (as the case) relative to the baseline retinal ischemia area-over time Proportion of patients with vascular leakage on FFA and OCT-A (as the case may be)-the change in FFA and OCT-A (as the case) relative to the baseline vascular leakage area over time-over time Changes in the fovea avascular area defined in SAP (Statistical Analysis Plan) and other exploratory output changes on OCT-A (as the case may be) relative to baseline-the proportion of patients with no retinal neovascularization over time ( According to the researcher's assessment)-the proportion of patients with no vitreous, preretinal or subretinal hemorrhage over time (according to the researcher's assessment)-the proportion of patients with no anterior segment (iris and corner corners) neovascularization over time -The proportion of patients requiring panretinal photocoagulation at any time during the study period-The absence of macular edema over time (defined as for Spectralis SD-OCT, CST ≤ 325 µm or for Cirrus SD-OCT or Topcon SD-OCT, The proportion of patients with ≤315 µm)-the proportion of patients with no intraretinal fluid over time-the proportion of patients with no subretinal fluid over time-the proportion of patients without both intraretinal fluid and subretinal fluid over time Proportion of patients-The proportion of patients who do not have intraretinal cysts over time-Changes in the scores of NEI VFQ-25 Proximal Activity Scale and Distance Activity Scale over time relative to the baseline NEI VFQ-25 Proximal Activity Scale score

Treatment schedule for Part 1 (Q4W administration ) In Part 1 of the study, patients will receive the following treatments:-Patients randomly assigned to team A will receive fluxipilimab Q4W from day 1 to week 20- Patients in group B will receive aflibercept Q4W from day 1 to week 20

The treatment schedule of Part 2 ( Personalized Treatment Interval (PTI) plan ) In Part 2 of the study, depending on the PTI dosing plan, all patients will visit clinical Q4W from week 24 to week 68 and receive sham treatment Or flucipilimab 6 mg IVT.

The fluxipilimab PTI decision will be automatically calculated based on the PTI criteria described in this section.

The decision of the study drug dosing interval in the PTI team is based on the algorithm described in this section. The flucipilimab administration visit is defined as the patient's visit when they receive fluxipilimab 6 mg IVT.

Starting from week 24, patients will receive flucipilimab at a frequency of Q4W until the CST meets the predetermined reference CST threshold (for Spectralis SD-OCT, <325 mm, or for Cirrus SD-OCT and Topcon SD-OCT , <315 mm), as determined by CRC. The reference CST (as described in Figure 8 and defined below) was used during the flucipilimab dosing visit to determine the fluxipilimab dosing interval. After determining the patient’s initial reference CST, if the CST value is stable (that is, it has not increased or decreased> 10%) and there is no relevant reference BCVA vision loss ≥ 10 letters, the patient will increase fluoride in a 4-week increase The interval between sipilimab dosing is eligible (as described in Figure 8 and defined below).

Reference to CST and reference to BCVA (see letters ^a and ^b in Figure 8 and the description of the figures) mean the following: a Reference to the central retinal thickness of the macula (CST): the CST value when the initial CST threshold is met. The reference CST was adjusted when the CST was reduced by> 10% from the previous reference CST of two consecutive study drug administration visits, and the value obtained was within 30 μm. The CST value obtained during subsequent visits will serve as the new reference CST, starting immediately from that visit. b Reference best corrected visual acuity (BCVA): the average of the three best BCVA scores obtained at any previous dosing visit.

The maximum and minimum treatment intervals that can be specified will be Q16W and Q4W respectively. Except for patients whose dosing interval has been shortened to Q4W, patients who have previously extended the dosing interval and have experienced disease progression (shortened trigger interval) will not be allowed to extend the interval again; the interval for these patients can be extended again, but only to be less than it The original maximum extension of the interval is 4 weeks. For example, if the interval between patients is shortened from Q12W to Q8W, for the remainder of the treatment period, the interval between patients will not extend beyond Q8W. If the patient interval is shortened from Q16W to Q4W, the patient interval can be extended to Q12W, but it cannot be extended back to Q16W.

Fluoro West Pittsburgh mAb (RO6867461 / RG7716 / VEGFang2-0016) interval measuring interval for decision making algorithms are summarized below and in FIG. 8, the algorithm is based on comparison to the reference and reference BCVA CST, horses fluoro West mAb The relative changes of CST and BCVA at the dosing visit. The flucipilimab dosing interval will be extended, maintained, or shortened as follows. -In the following cases, the CST value increases or decreases by ≤ 10% in the interval extension for 4 weeks without the associated BCVA decrease ≥ 10 letters-The interval is maintained if any of the following criteria is met: CST value decrease> 10% CST Value reduction ≤ 10%, with associated BCVA decrease ≥ 10 letters CST value increase> 10% and ≤ 20%, without relevant BCVA decrease ≥ 5 letters -the interval is shortened by 4 if any of the following criteria is met Week : CST value increased> 10% and ≤ 20%, with associated BCVA decrease ≥ 5 to <10 letters CST value increased> 20%, and no related BCVA decrease ≥ 10 letters CST value increased ≤ 10%, accompanied Related BCVA decrease ≥ 10 letters - In the following cases, the interval is shortened to Q4W CST value increase> 10%, accompanied by related BCVA decrease ≥ 10 letters

As outlined above, the algorithm for personalized drug treatment interval decision is based on the relative change of CST and the absolute change of BCVA compared to the reference CST and BCVA, respectively.

The algorithm can be implemented by a computing system or device. The computing system or device may include a web interface, mobile application, software program or any clinical decision support tool. For example, the patient's CST and BCVA scores can be uploaded to the web interface of the personalized dosing interval software tool. Using the uploaded CST and BVCA, the tool can automatically calculate and output the timing of the next dose. The tool can further provide dosing schedules or notifications, monitor and generate visualized results of dosing interval changes for a given patient, generate visualized results of dosing interval changes for patient groups, and aggregate the received CST and BCVA data to determine Trend, or a combination.

The dosing schedule or notification may include a calendar date showing the scheduled dosing visit and a calendar reminder to notify the clinician or the patient who is about to undergo the dosing visit. The visualization result of the change in the dosing interval may include, for example, the schematic display in FIG. 8. In one case, the patient's dosing interval adjustment can be displayed in one color, and the patient's immediate previous dosing interval adjustment can be displayed in another color. For example, the patient can first extend their interval by 4 weeks, and then maintain their personalized treatment interval. The tool can generate a visualized result of the patient's personalized interval progression by displaying the "interval maintenance" area of the schematic diagram in green in FIG. 8 and the "interval extension by 4 weeks" in yellow. Green can reflect the patient's latest interval calculation and yellow can depict the result of the patient's immediate previous interval calculation. With this visualized result, the user of the tool can quickly determine that the patient's disease progression is improving, but it has not improved to the extent that the treatment interval can be extended more.

The tool can further aggregate patient and dosing schedule data and generate visualized results of aggregated data. Similar to the color coding example described previously, this type of data analysis can include the visualization of the administration changes of a single patient. Alternatively, the visualized results can show dosing adjustments for the patient group. For example, a visual result can show which patients have interval extension and which patients have interval shortening. This visualized result can be organized by various characteristics, such as patient age, previous treatment, disease condition, administered antibody, clinical trial group, and so on. The tool can also aggregate patient CST and BCVA data and generate visual results based on the data. Visualized results can show trends in data to facilitate or generate longitudinal analysis. These visual results can include reminders, curves, analytical workflow interfaces, or any graphical interface.

The tool can respond to or together with eye assessments and images to generate dosing schedule output or visualization results. In one embodiment, the tool can directly calculate the patient's CST or BVCA. Regarding CST, the tool can receive or directly capture eye images. The tool can further use image segmentation, image recognition or machine learning techniques to calculate CST based on eye images. Regarding BCVA, the tool can virtually manage eye assessments, prompt and collect patient user input via a user interface or via an eye tracking mechanism. Alternatively, the tool can receive, store, and track eye assessment data. In this way, the tool can track the disease progression of each patient and adjust the dosing schedule accordingly.

Embodiments of the present invention may include a method of providing a personalized dosing schedule based on a personalized treatment interval (PTI) for the treatment of patients suffering from ocular vascular diseases selected from those secondary to the central retinal vein Obstruction, macular edema secondary to semiretinal vein occlusion or branch vein occlusion, the method includes: receiving patient data in a computing system, the patient data including the patient’s CST and best corrected visual acuity (BCVA); using the calculation The system extends, shortens or maintains the dosing interval based on the received patient data compared with the respective reference CST and BCVA; and obtains the PTI according to the dosing interval. In the case of an increase or decrease in CST value of ≤ 10%, and no related BCVA decrease of ≥ 10 letters, the exemplary dosing interval is extended by 4 weeks. If any of the following criteria is met, the exemplary dosing interval is maintained: CST value reduction> 10%; or CST value reduction ≤ 10%, with associated BCVA reduction ≥ 10 letters, or CST value increase> 10% and ≤ 20%, and no related BCVA decrease ≥ 5 letters. If any of the following criteria is met, the exemplary dosing interval is shortened by 4 weeks: CST value increase> 10% and ≤ 20%, with associated BCVA decrease ≥ 5 to <10 letters, or CST value Increase> 20% without related BCVA decrease ≥ 10 letters; or CST value increase ≤ 10%, accompanied by related BCVA decrease ≥ 10 letters. In the case of a CST value increase of> 10%, with a related BCVA decrease of ≥ 10 letters, the exemplary dosing interval is shortened to Q4W.

Provide personalized dosing schedule based on personalized treatment interval (PTI) for the treatment of eyes suffering from macular edema secondary to central retinal vein occlusion, secondary to semiretinal vein occlusion, or secondary to branch vein occlusion This method for patients with vascular disease may further include receiving updated patient data in a computing system; using the computing system to continuously update or maintain the dosing interval based on the updated patient data; and generate visualization based on the updated or maintained dosing interval Results, user interface or notifications.

The embodiments of the present invention also include the use of personalized drug delivery schedules based on personalized treatment intervals (PTI) (for the treatment of central retinal vein occlusion, semi-retinal vein occlusion, or branch vein occlusion). Macular edema), where the computing system obtains the PTI by: receiving patient data including the patient’s CST and best corrected visual acuity (BCVA), and extending, based on the received patient data compared with the respective reference CST and BCVA Shorten or maintain dosing intervals. In the case of an increase or decrease in CST value of ≤ 10%, and no related BCVA decrease of ≥ 10 letters, the exemplary dosing interval is extended by 4 weeks. If any of the following criteria is met, the exemplary dosing interval is maintained: CST value reduction> 10%; or CST value reduction ≤ 10%, with associated BCVA reduction ≥ 10 letters, or CST value increase> 10% and ≤ 20%, and no related BCVA decrease ≥ 5 letters. If any of the following criteria is met, the exemplary dosing interval is shortened by 4 weeks: CST value increase> 10% and ≤ 20%, with associated BCVA decrease ≥ 5 to <10 letters, or CST value Increase> 20% without related BCVA decrease ≥ 10 letters; or CST value increase ≤ 10%, accompanied by related BCVA decrease ≥ 10 letters. In the case of a CST value increase of> 10%, with a related BCVA decrease of ≥ 10 letters, the exemplary dosing interval is shortened to Q4W.

Ocular assessment given unless otherwise indicated, the eye will perform assessment of both eyes at a given time point based on the activity schedule. Evaluation includes:-Refraction and BCVA evaluated on the ETDRS visual acuity chart at a starting test distance of 4 meters (performed before eye expansion)-IOP measurement of both eyes (performed before eye expansion)-Fissure Light examination (used to grade the anterior muscles and vitreous cells)-Mydriatic binocular indirect high-power ophthalmoscope-Finger calculation test followed by hand movements and light performed within about 15 minutes after the study treatment of the study eye Perception test (when needed)-It takes 30 (±15) minutes after the study treatment is administered to perform post-dose IOP (intraocular pressure) measurement only in the study eye

If there are no safety issues after 30 (±15) minutes after the study treatment is administered, the patient will be allowed to leave the clinic. If the IOP value is in the concerns of the treatment manager/unshielded investigator, the patient will remain in the clinic and will be managed according to the clinical judgment of the treatment manager/unshielded investigator. When appropriate, adverse events will be recorded on the Electronic Case Report Form (eCRF) for adverse events. -The IOP measurement method used for the patient must remain constant throughout the study eye imaging

After randomization, if the patient has scheduled or scheduled visits for color fundus photography (CFP) or fundus fluorescein angiography (FFA) eye images (for example, due to broken equipment) If the study visit is missed, the image should be obtained at the next scheduled visit in which the patient participates.

Eye imaging includes the following content : -FFA for studying eyes-CFP for studying eyes-Spectral domain optical coherent tomography (SD-OCT) or scanning source OCT (SS-OCT) images for studying eyes-For those with OCT-A capability The OCT-A of the research eye selected according to the situation at the site (provide the sampling according to the situation approved by the site)

For patients diagnosed with bilateral RVO at the time of screening, CFP and OCT images of the other eye will also be captured and stored at the CRC.

Results The main efficacy analysis included all randomized patients, among which the patients were grouped according to the treatment specified by the randomized group.

The main efficacy variable is the change in BCVA. The main power analysis will be performed using a mixed model (MMRM) such as a repeated measurement model.

Best corrected vision Measure BCVA as described. The main efficacy outcome measure is shown in the graph showing the main efficacy endpoint: the change in BCVA of the patient over time relative to the baseline. According to the research procedure described above, the bispecific anti-VEGF/ANG2 antibody RO6867461 (fluorine) will contain the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20. Sipilimumab) (6.0 mg intravitreal administration as described in group A using a personalized treatment interval) was compared with group B (aflibercept (Eylea®) in Part 1 of the study).

The change in central retinal thickness (CST) of the macula from baseline ( study eye ) The key secondary endpoint is the change from baseline CST (central retinal thickness of the macula). CST (and retinal thickness) was measured via optical coherence tomography (OCT). The results are shown in a graph in which the bispecific anti-VEGF/ANG2 containing the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 are displayed over time The CST change of antibody RO6867461 (fluxipilimab) (administered intravitreally at 6.0 mg as described in group A using a personalized treatment interval). According to the research procedure described above, the antibody was combined with, for example, group A. B (Aflibercept (Eylea®) in Part 1 of the study) for comparison.

It can therefore show other results of eye assessment and imaging.

Example 4 The kinetic affinity of anti-VEGF/ANG2 antibody to VEGF, Ang2, FcγR and FcRn binding to VEGF isoforms, including species cross-reactivity was assessed by using the amine coupling kit supplied by GE Healthcare at pH 5.0 About 12000 resonance units of the coupled capture system (10 µg/ml goat anti-human F(ab)'₂; command code: 28958325; GE Healthcare Bio-Sciences AB, Sweden) on the CM5 chip (GE Healthcare BR-1005-30) (RU). The sample and system buffer is PBS-T (10 mM phosphate buffered saline, including 0.05% Tween® 20) pH 7.4. The flow cell was set to 25°C, and the sample block was set to 12°C, and pre-coated twice with the operating buffer. The bispecific antibody was captured by injecting a 50 nM solution at a flow rate of 5 µl/min for 30 seconds. The correlation was measured by injecting human hVEGF121, mouse mVEGF120, or rat rVEGF164 in the solution at various concentrations at a flow rate of 30 µl/min starting at 300 nM in a 1:3 dilution for 300 seconds. The dissociation phase was monitored for up to 1200 seconds and was triggered by switching from the sample solution to the operating buffer. At a flow rate of 30 µl/min, the surface was regenerated by washing with a glycine pH 2.1 solution for 60 seconds. The overall refractive index difference is corrected by subtracting the response obtained from the goat anti-human F(ab') _{2 surface.} Also subtract the blank injection (=second reference). To calculate the apparent K _D and other kinetic parameters, the Langmuir 1:1 model was used. The results are shown in Table 5.

Ang2 solution affinity including assessment of species cross-reactivity The solution affinity measures the affinity of the interaction by measuring the concentration of the free interaction partner in the equilibrium mixture. Solution affinity analysis involves mixing the <VEGF-ANG-2> bispecific antibody (maintained at a constant concentration) with different concentrations of ligand (= Ang2). The largest possible resonance unit (for example, 17000 resonance units (RU)) of the antibody was immobilized on the surface of a CM5 chip (GE Healthcare BR-1005-30) at pH 5.0 using an amine coupling kit supplied by GE Healthcare. The sample and system buffer is HBS-P pH 7.4. The flow cell was set to 25°C, and the sample block was set to 12°C, and pre-coated twice with operating buffer. To generate a calibration curve, Ang2 with increasing concentrations was injected into a BIAcore™ flow cell containing immobilized VEGF-ANG-2>bispecific antibodies. The amount of bound Ang2 is determined in resonance units (RU) and plotted against concentration. The solution of each ligand (for VEGF-ANG-2>bispecific antibody, 11 concentrations of 0 to 200 nM) was incubated with 10 nM Ang2 and allowed to reach equilibrium at room temperature. The free Ang2 concentration is determined based on the calibration curve generated before and after the reaction of a solution with a known amount of Ang2 is measured. Using model 201, using the free Ang2 concentration as the y-axis and the inhibitory antibody concentration as the x-axis, XLfit4 (IDBS software) was used to set 4 parameters for fitting. Affinity is calculated by measuring the inflection point of this curve. The surface is regenerated by washing the surface for 30 seconds with a 0.85% H ₃ PO ₄ solution at a flow rate of 30 µl/min. The overall refractive index difference is corrected by subtracting the response obtained from the blank coupling surface. The results are shown in the table below.

FcRn steady state affinity For FcRn measurement, steady state affinity is used to compare bispecific antibodies with each other. Human FcRn was diluted into coupling buffer (10 µg/ml, sodium acetate, pH 5.0) and immobilized on C1-chip (GE Healthcare BR -1005-35) on. The flow cell was set to 25°C, and the sample block was set to 12°C, and pre-coated twice with operating buffer. The sample and system buffer is PBS-T (10 mM phosphate buffered saline, including 0.05% Tween® 20) pH 6.0. To evaluate the different IgG concentration of each antibody, 62.5 nM, 125 nM, 250 nM, 500 nM concentrations were prepared. The flow rate was set to 30 µl/min and different samples were continuously injected onto the wafer surface, and an association time of 180 seconds was selected. The surface was regenerated by injecting PBS-T pH 8 at a flow rate of 30 µl/min for 60 seconds. The overall refractive index difference is corrected by subtracting the response obtained from the blank surface. Also subtract the buffer injection (=second reference). To calculate the steady-state affinity, a method based on the Bia-Evaluation software is used. In short, the RU value (the maximum value of RU) is plotted against the analyzed concentration to obtain a dose-response curve. Based on the 2 parameter fit, the upper asymptote is calculated, allowing the determination of the half-maximum RU value and therefore the affinity. The results are shown in the table below. Similarly, the affinity to cynomolgus monkey, mouse and rabbit FcRn can be determined.

FcγRIIIa measurement For FcγRIIIa measurement, direct binding analysis was used. By using the amine coupling kit supplied by GE Healthcare to couple the capture system (1 µg/ml Penta-His; Qiagen) on a CM5 chip (GE Healthcare BR-1005-30) at pH 5.0 with approximately 3000 resonance units ( RU). The sample and system buffer is HBS-P+ pH 7.4. The flow cell was set to 25°C, and the sample block was set to 12°C, and pre-coated twice with operating buffer. The FcγRIIIa-His-antibody was captured by injecting 100 nM solution at a flow rate of 5 µl/min for 60 seconds. Measure binding by injecting 100 nM bispecific antibody or monospecific control antibody (anti-Dig of IgG1 subclass and IgG4 subclass antibody) at a flow rate of 30 µl/min for 180 seconds. At a flow rate of 30 µl/min, wash the surface with a glycine pH 2.5 solution for 120 seconds to regenerate the surface. Since FcγRIIIa binding is different from the Langmuir 1:1 model, only binding/no binding is determined by this analysis. In a similar manner, FcγRIa and FcγRIIa binding can be determined. The results are shown in the table below, where by introducing the mutation P329G LALA, no more binding to FcγRIIIa can be detected.

Evaluation of the binding between independent VEGF and Ang2 and <VEGF-ANG-2> bispecific antibody By using the amine coupling kit supplied by GE Healthcare, the capture system (10 µg/ml goat anti-human IgG) was coupled to the CM4 chip (GE Healthcare BR-1005-34) at pH 5.0; GE Healthcare Bio-Sciences AB, Sweden ) Of about 3500 resonance units (RU). The sample and system buffer is PBS-T (10 mM phosphate buffered saline, including 0.05% Tween® 20) pH 7.4. The temperature of the flow cell was set to 25°C and the temperature of the sample block was set to 12°C. Before capture, the flow cell was pre-coated twice with operating buffer.

The bispecific antibody was captured by injecting a 10 nM solution at a flow rate of 5 µl/min for 60 seconds. Analyze the independent binding of each ligand to the bispecific antibody by measuring the active binding capacity of each ligand added sequentially or simultaneously (at a flow rate of 30 µl/min): 1. Inject human VEGF at a concentration of 200 nM for 180 seconds (identify a single binding of the antigen). 2. Inject human Ang2 at a concentration of 100 nM for 180 seconds (identify a single binding of the antigen). 3. Inject human VEGF at a concentration of 200 nM for 180 seconds, and then inject human Ang2 at a concentration of 100 nM for 180 seconds (identify the binding of Ang2 in the presence of VEGF). 4. Inject human Ang2 at a concentration of 100 nM for 180 seconds, and then inject human VEGF at a concentration of 200 nM (identify the binding of VEGF in the presence of Ang2). 5. Co-inject human VEGF with a concentration of 200 nM and human Ang2 with a concentration of 100 nM for 180 seconds (identify the combination of VEGF and Ang2 at the same time).

Regenerate the surface by washing _{with a 3mM MgCl 2} solution for 60 seconds at a flow rate of 30 µl/min. The overall refractive index difference is corrected by subtracting the response obtained from the goat anti-human IgG surface.

If the final signals obtained by methods 3, 4, and 5 are equal to or similar to the sum of the individual final signals of methods 1 and 2, then the bispecific antibody can bind two antigens independently of each other. The results are shown in the table below, which shows that VEGFang2-0016 (= RO6867461) can bind to VEGF and ANG2 independently of each other.

Evaluation of the simultaneous binding of VEGF and Ang2 with the <VEGF-ANG-2> bispecific antibody Firstly, by using the amine coupling kit supplied by GE Healthcare on a CM4 chip (GE Healthcare BR-1005-34) at pH 5.0 Approximately 1600 resonance units (RU) of VEGF (20 µg/ml) are coupled on top. The sample and system buffer is PBS-T (10 mM phosphate buffered saline, including 0.05% Tween® 20) pH 7.4. The flow cell was set to 25°C, and the sample block was set to 12°C, and pre-coated twice with operating buffer. Next, a 50 nM solution of the bispecific antibody was injected at a flow rate of 30 µl/min for 180 seconds. Third, hAng-2 was injected at a flow rate of 30 µl/min for 180 seconds. The binding response of hAng-2 depends on the amount of bispecific antibody that binds to VEGF and shows simultaneous binding. The surface is regenerated by washing _{with 0.85% H 3} PO ₄ solution for 60 seconds at a flow rate of 30 µl/min. At the same time, the binding is shown by the additional specific binding signal of hAng2 which binds to the previous VEGF <VEGF-ANG-2> bispecific antibody. Table: Results: Kinetic affinity to VEGF isoforms from different species VEGFang2-0016 - Apparent affinity Human VEGF 121 ≤ 1 pM (exceeding Biacore specifications) Mouse VEGF 120 No binding Rat VEGF 164 14 nM Table: Results: Solution affinity to Ang2 VEGFang2-0016 KD [nM] Human Ang2 20 Crab-eating macaque Ang2 13 Mouse Ang2 13 Rabbit Ang2 11 Table: Results: Affinity to FcRn of <VEGF-ANG-2> bispecific antibody VEGFang2-0016 [ Affinity] Human FcRn No binding Crab-eating macaque FcRn No binding Mouse FcRn No binding Table: Results: Binding to FcγIIIa VEGFang2-0016 FcγRIIIa No binding Table: Results: Independent binding of VEGF and Ang2 to the <VEGF-ANG-2> bispecific antibody 1) Ang2 [RUmax] 2) VEGF [RUmax] 3) VEGF first , then Ang2 [RUmax] 4) Ang2 first , then VEGF [RUmax] 5) Co-injection of Ang2+VEGF [RUmax] VEGFang2-0016 174 50 211 211 211

Figure 1 : Figure 1 shows an overview of the study design for nAMD.a At the 20th and 24th week, the patient will undergo a disease activity assessment. Patients with anatomical or functional signs of disease activity at these time points will receive Q8W or Q12W administration, instead of Q16W administration, respectively. b The primary endpoint is based on the change from the baseline BCVA of the average at Week 40, Week 44, and Week 48 (as assessed on the ETDRS chart at a starting distance of 4 meters). c Starting from week 60 (when all patients in team A are scheduled to receive faricimab), patients in team A will be administered according to the PTI dosing schedule (between Q8W and Q16W) treatment. BCVA=best corrected visual acuity; ETDRS=early treatment of diabetic retinopathy; IVT=intravitreal; PTI=personalized treatment interval; Q8W=every 8 weeks; Q12W=every 12 weeks; Q16W=every 16 weeks; W=week . Figure 2 : Figure 2 shows an overview of the research design used for DME. Team A (Q8W administration): Patients randomized to team A will receive Q4W 6-mg IVT RO6867461 (fluxipilimab) injection to the 20th Weeks, followed by Q8W 6-mg IVT RO6867461 (fluxipilimab) injection to the 96th week, followed by the final study visit at the 100th week. Team B (Personalized Treatment Interval): Patients randomized to Team B will receive Q4W 6-mg IVT RO6867461 (fluxipilimab) injection until at least the 12th week, followed by 6-mg IVT RO6867461 (fluoro The PTI administration of sipilimab injection (see PTI administration guidelines below) until the 96th week, followed by the final study visit at the 100th week. Team group C (comparative agent team group) (Q8W administration): Patients randomized to team group C will receive Q4W 2-mg IVT aflibercept injection until week 16, followed by Q8W 2-mg IVT Aflibercept was injected until the 96th week, followed by the final study visit at the 100th week. Patients in all three treatment team groups will complete the Q4W scheduled study visit for the entire study duration (100 weeks). Sham procedures will be administered to patients in all three treatment team groups at the time of the applicable visit to maintain shielding between treatment teams. IVT = intravitreal; Q8W = every 8 weeks; PTI = personalized treatment interval (for additional details, see section 3.1.2); W = weeks. a The 1-year definition for the primary efficacy endpoint (defined as the change in BCVA from the baseline, as measured on the ETDRS chart at a starting distance of 4 meters at 1 year) is the 48th week and the first Average of 52 and 56 week visits. Figure 3 : Schematic personalized treatment interval for DME-Figure 3 outlines the algorithm for interval decision, which is based on the relative changes of CST and BCVA compared to the reference CST and the reference BCVA. The meaning of * and ** in Figure 3: * Reference macular central retinal thickness (CST): CST value when it meets the initial CST threshold criteria. The reference CST was adjusted when the CST was reduced by> 10% from the previous reference CST of two consecutive study drug administration visits, and the value obtained was within 30 μm. The CST value obtained during subsequent visits will serve as the new reference CST, starting immediately from that visit. ** Reference best corrected visual acuity (BCVA): the average of the three best BCVA scores obtained at any previous dosing visit. Figure 4 : Schematic comparison of durability (time to retreatment) and efficacy (DME) in DME and nAMD based on published results with other treatment options for DME and nAMD (comparison drug Lucentis® (Lambizumab) Anti), Eylea® (aflibercept), brolucizumab and VA2 (RO6867461/fluxipilimab). Figure 5 : Comparing the bispecific anti-VEGF/ANG2 antibody RO6867461 (fluxipilizumab) at 12 and 16 week intervals with lambilizumab (Lucentis®) at 4 week intervals in patients with neovascularization Patients with age-related macular degeneration (nAMD) have an increase in BCVA relative to baseline. Figure 6 : Based on the time required for retreatment of the disease activity to reach diabetic macular edema (DME), the disease activity is assessed by the following two: BCVA decrease ≥ 5 letters and CST increase ≥ 50 µm (after stopping After administration (after 20 weeks or once every 6 months = the time since the most recent intravitreal (IVT) administration). Combine bispecific anti-VEGF/ANG2 antibody RO6867461 (fluxipilizumab) with lambilizumab (Lucentis®) to compare and show longer time to retreatment. Figure 7 : Figure 7 shows an overview of the study design for the treatment of macular edema secondary to retinal vein occlusion (RVO) IVT = intravitreal; PTI = Personalized treatment interval; Q4W = every 4 weeks; W = week. Figure 8 : Schematic personalized treatment interval for the treatment of macular edema secondary to retinal vein occlusion (RVO)-Figure 8 outlines the algorithm used for interval decision-making The method is based on the relative changes of CST and BCVA compared with the reference CST and the reference BCVA. BCVA = best corrected visual acuity; CST = macular center retinal thickness; Q4W = every 4 weeks. a Initial reference CST = in line with the initial CST Limit criteria but not earlier than the CST value at week 20. The reference CST is adjusted when the CST is reduced by> 10% compared to the previous reference CST of two consecutive visits of fluxipilimab administration, and the obtained The value is within 30 µm. The CST value obtained at a later visit will serve as the new reference CST, starting immediately from that visit. b Reference BCVA = the three best BCVA scores obtained during any previous dosing visit The average value.

Claims (26)

The use of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) in the manufacture of medicines for the treatment of neovascular AMD (nAMD) and diabetes Patients with ocular vascular disease of DME or suffering from ocular vascular disease selected from neovascular AMD (nAMD) and diabetic macular edema (DME), wherein the treatment includes a personalized treatment interval (PTI). The use of claim 1, wherein the drug is used to treat neovascular age-related macular degeneration (nAMD) or patients suffering from nAMD. Such as the use of claim 2, wherein the treatment includes a personalized treatment interval, wherein a) The patient is first treated with the bispecific VEGF/ANG2 antibody for 4 times at a dosing interval every 4 weeks (Q4W); b) Assessment of disease activity at the 20th and 24th week, in which the determination of whether the disease activity meets one of the following criteria: i) Compared with the average CST value of the two previous scheduled visits, the central retinal thickness (CST) of the macula has increased> 50 μm. The 20th week assessment is for the 12th and 16th week visits and the 24th week is for the assessment system. For visits in weeks 16 and 20, or ii) Compared with the lowest CST value recorded during any of the two previous scheduled visits, the CST increased by ≥ 75 μm; iii) Compared with the average best corrected visual acuity (BCVA) value of the two previous scheduled visits, the BCVA decreased by ≥ 5 letters, iv) Compared with the highest BCVA value recorded during any of the two previous scheduled visits, the BCVA decreased by ≥ 10 letters, or v) New macular hemorrhage due to nAMD activity c) Follow the patient i) Patients who meet the criteria for disease activity in the 20th week will be treated at an 8-week (Q8W) dosing interval starting from the 20th week (the first Q8W dose will be given at the 20th week); ii) Patients who meet the criteria for disease activity at week 24 will be treated at every 12-week (Q12W) dosing interval starting from week 24 (where the first Q12W dosing will be given at week 24); and iii) Patients who do not meet the criteria for disease activity in the 20th and 24th weeks will be treated at 16-week (Q16W) dosing intervals starting from the 28th week (where the first Q16W dosing will be given at the 28th week) . Such as the use of claim 3, where after the 60th week, the personalized treatment interval will be extended, shortened or maintained, where a) When all the following criteria are met, the interval is extended by 4 weeks (to the maximum Q16W): i) Compared with the average value of the last two study drug administration visits, CST is stable. Stability is defined as the change of CST less than 30 µm and compared with the lowest measured value of the drug administration visit in the study, CST No increase ≥ 50 µm, ii) Compared with the average of the last two study drug administration visits, BCVA did not decrease by ≥ 5 letters, and compared with the highest study drug administration visit measurement value, BCVA did not decrease by ≥ 10 letters , iii) No new macular hemorrhage b) the interval In the case of meeting one of the following criteria, shorten 4 weeks (to a minimum of Q8W), or In the event that two or more of the following criteria are met or one criterion includes new macular hemorrhage, shorten the interval to 8 weeks: i) Compared with the average of the last two dosing visits, the CST increased by ≥ 50 µm, or compared with the lowest dosing visit measurement value, the CST increased by ≥ 75 µm; ii) Compared with the average of the last two dosing visits, the BCVA decreased by ≥ 5 letters, or compared with the highest dosing visit measurement value, the BCVA decreased by ≥ 10 letters; iii) New macular hemorrhage. Such as the use of claim 1, wherein the drug is used to treat diabetic macular edema (DME) or patients suffering from DME. Such as the use of claim 5, wherein the treatment includes a personalized treatment interval (PTI), wherein a) The patient is first treated with the bispecific VEGF/ANG2 antibody every 4 weeks (Q4W) dosing interval until the central retinal thickness (CST) of the macula measured on or after the 12th week meets the predetermined reference CST Up to the threshold b) The dosing interval is then increased by 4 weeks to the initial Q8W dosing interval; c) From now on, according to the assessments made during the dosing visits, the dosing interval will be extended, shortened or maintained. The assessments are based on the CST and best corrected visual acuity (BCVA) and the respective reference CST and The relative change compared to BCVA; among them i) In the following cases, the interval is extended by 4 weeks, The CST value increases or decreases by ≤ 10%, and there is no related BCVA decrease by ≥ 10 letters; ii) Maintain this interval in the following cases: The CST is reduced by> 10%, or The CST value increases or decreases by ≤ 10%, and the associated decrease in BCVA is ≥ 10 letters, or The CST value increased by more than 10% and less than 20%, and there is no related BCVA decreased by more than 5 letters; iii) In the following cases, the interval is shortened by 4 weeks The CST value increased by> 10% and ≤ 20%, with the associated decrease in BCVA by ≥ 5 to <10 letters; or The CST value increased by ＞ 20%, and there was no related BCVA decrease by ≥ 10 letters; iv) When the CST value increases> 10%, and the associated BCVA decreases ≥ 10 letters, the interval is shortened by 8 weeks; Among them, when the initial CST threshold is met, the respective reference macular central retinal thickness (CST) is the CST value, and the CST is reduced by> 10% compared to the previous reference CST of two consecutive dosing visits Adjust the reference CST, and the obtained values are within 30 µm, so that the CST value obtained during subsequent visits will serve as the new reference CST; and The reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any previous dosing visit. Such as the use of claim 6, wherein the dosing interval can be adjusted in a 4-week increase to the maximum every 16 weeks (Q16W) and the minimum Q4W. The use of a bispecific antibody that binds to human vascular endothelial growth factor (VEGF) and human angiopoietin-2 (ANG-2) in the manufacture of drugs, which are selected from the group of drugs secondary to central retinal vein occlusion, secondary Ocular vascular disease caused by hemi-retinal vein occlusion or macular edema secondary to branch vein occlusion or treatment suffering from macular diseases selected from the group consisting of secondary central retinal vein occlusion, secondary semi-retinal vein occlusion or secondary occlusion Patients with ocular vascular disease with ocular edema, where the treatment includes a personalized treatment interval (PTI), where a) The patient is first treated with the bispecific VEGF/ANG2 antibody at a dosing interval of 4 weeks (Q4W) from day 1 to week 20; b) From the 24th week, the patient receives the bispecific VEGF/ANG2 antibody at the Q4W frequency until the central retinal thickness (CST) of the macula meets the predetermined reference CST threshold; c) From now on, according to the assessments performed during the dosing visits, the dosing interval will be extended, shortened or maintained. The assessments are based on the CST and best corrected visual acuity (BCVA) and the respective reference CST and BCVA. Relative change among them i) In the following cases, the interval is extended by 4 weeks The CST value increased or decreased by ≤ 10% without a related BCVA decrease by ≥ 10 letters; or ii) Maintain this interval if any of the following criteria is met: The CST value is reduced by> 10%; or The CST value is reduced by ≤ 10%, with associated BCVA reduction by ≥ 10 letters, or The CST value increased by more than 10% and less than 20%, and there is no related BCVA decreased by more than 5 letters; iii) If any of the following criteria is met, the interval is shortened by 4 weeks: The CST value increased by> 10% and ≤ 20%, with associated BCVA decrease by ≥ 5 to <10 letters, or The CST value increased by> 20% without a related decrease in BCVA by ≥ 10 letters; or The CST value increased by ≤ 10%, and the associated BCVA decreased by ≥ 10 letters; iv) In the following cases, the interval is shortened to Q4W The CST value increased by> 10%, and the associated BCVA decreased by ≥ 10 letters, Among them, when the initial CST threshold is met, the respective reference macular central retinal thickness (CST) is the CST value, and the CST is reduced by> 10% compared to the previous reference CST of two consecutive dosing visits Adjust the reference CST, and the obtained values are within 30 µm, so that the CST value obtained during subsequent visits will serve as the new reference CST; and The reference best corrected visual acuity (BCVA) is the average of the three best BCVA scores obtained at any previous dosing visit. Such as the use of claim 8, wherein the dosing interval can be adjusted to a maximum of every 16 weeks (Q16W) and a minimum of Q4W. The use according to any one of claims 1 to 9, wherein the bispecific antibody that binds to human VEGF and human ANG2 is a bispecific bivalent anti-VEGF/ANG2 antibody, which comprises a first antibody that specifically binds to human VEGF The antigen-binding site and the second antigen-binding site that specifically binds to human ANG-2, wherein i) The first antigen binding site that specifically binds to VEGF includes the CDR3H region of SEQ ID NO: 1, the CDR2H region of SEQ ID NO: 2, and the CDR1H region of SEQ ID NO: 3 in the heavy chain variable domain, And the light chain variable domain includes the CDR3L region of SEQ ID NO: 4, the CDR2L region of SEQ ID NO: 5, and the CDR1L region of SEQ ID NO: 6; and ii) The second antigen binding site that specifically binds to ANG-2 includes the CDR3H region of SEQ ID NO: 9, the CDR2H region of SEQ ID NO: 10, and the CDR1H of SEQ ID NO: 11 in the heavy chain variable domain Region, and includes the CDR3L region of SEQ ID NO: 12, the CDR2L region of SEQ ID NO: 13 and the CDR1L region of SEQ ID NO: 14 in the light chain variable domain, And where iii) The bispecific antibody contains the constant heavy chain region of the human IgG1 subclass, which contains the mutations I253A, H310A and H435A and the mutations L234A, L235A and P329G, wherein these numbers are based on the EU index of Kabat. Such as the purpose of claim 10, where i) The first antigen binding site that specifically binds to VEGF includes the amino acid sequence of SEQ ID NO: 7 as the heavy chain variable domain VH, and includes the amino acid sequence of SEQ ID NO: 8 as the light chain Variable domain VL, and ii) The second antigen binding site that specifically binds to ANG-2 includes the amino acid sequence of SEQ ID NO: 15 as the heavy chain variable domain VH, and includes the amino acid sequence of SEQ ID NO: 16 as the light Chain variable domain VL. The use according to any one of claims 1 to 9, wherein the bispecific antibody that binds to human VEGF and human ANG2 comprises SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 amino acid sequence. The use according to any one of claims 1 to 9, wherein the bispecific antibody is faricimab. The use of claim 10, wherein the bispecific antibody system is administered in a dose of about 5 to 7 mg. The use of claim 10, wherein the bispecific antibody system is administered in a dose of about 6 mg. The use of claim 14, wherein the bispecific antibody system is administered at a concentration of about 120 mg/ml. The use according to any one of claims 1 to 9, wherein the patient suffering from ocular vascular disease has not been previously treated with anti-VEGF therapy. The use according to any one of claims 1 to 9, wherein the patient suffering from ocular vascular disease has been previously treated with anti-VEGF therapy. Such as the use of any one of claims 1 to 9, wherein the antibody system is administered according to the measurement of the software tool. A method for patients suffering from nAMD to provide a personalized dosing schedule based on a personalized treatment interval (PTI), the method includes: Receive patient data in the computing system, the patient data includes the patient's CST and best corrected visual acuity (BCVA), as well as optional information about the assessment of new macular hemorrhage; and Use this calculation system to extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; and PTI is obtained according to the dosing interval, where a) When all the following criteria are met, the interval is extended by 4 weeks (to the maximum Q16W): i) Compared with the average value of the last two study drug administration visits, CST is stable. Stability is defined as the change of CST less than 30 µm and compared with the lowest measured value of the drug administration visit in the study, CST No increase ≥ 50 µm, ii) Compared with the average of the last two study drug administration visits, BCVA did not decrease by ≥ 5 letters, and compared with the highest study drug administration visit measurement value, BCVA did not decrease by ≥ 10 letters , iii) No new macular hemorrhage b) The interval shall be shortened by 4 weeks (to a minimum of Q8W) if one of the following criteria is met, or In the event that two or more of the following criteria are met or one criterion includes new macular hemorrhage, shorten the interval to 8 weeks: i) Compared with the average of the last two dosing visits, the CST increased by ≥ 50 µm, or compared with the lowest dosing visit measurement value, the CST increased by ≥ 75 µm; ii) Compared with the average of the last two dosing visits, the BCVA decreased by ≥ 5 letters, or compared with the highest dosing visit measurement value, the BCVA decreased by ≥ 10 letters; iii) New macular hemorrhage. A method for patients suffering from DME to provide a personalized dosing schedule based on a personalized treatment interval (PTI), the method includes: Receive patient data in the computing system, which includes the patient’s CST and best corrected visual acuity (BCVA); Use this calculation system to extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; and PTI is obtained according to the dosing interval, where i) In the following cases, the interval is extended by 4 weeks, The CST value increases or decreases by ≤ 10%, and there is no related BCVA decrease by ≥ 10 letters; ii) Maintain this interval in the following cases: The CST is reduced by> 10%, or The CST value increases or decreases by ≤ 10%, and the associated decrease in BCVA is ≥ 10 letters, or The CST value increased by more than 10% and less than 20%, and there is no related BCVA decreased by more than 5 letters; iii) In the following cases, the interval is shortened by 4 weeks The CST value increased by> 10% and ≤ 20%, with the associated decrease in BCVA by ≥ 5 to <10 letters; or The CST value increased by ＞ 20%, and there was no related BCVA decrease by ≥ 10 letters; iv) In the case where the CST value increases> 10%, and the associated BCVA decreases ≥ 10 letters, the interval is shortened by 8 weeks. A method for patients suffering from ocular vascular diseases based on personalized treatment interval (PTI), which is selected from secondary to central retinal vein occlusion and secondary to semi-retinal vein occlusion Or macular edema secondary to branch vein occlusion, this method includes: Receive patient data in the computing system, which includes the patient’s CST and best corrected visual acuity (BCVA); Use this calculation system to extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; and PTI is obtained according to the dosing interval, where i) In the following cases, the interval is extended by 4 weeks The CST value increased or decreased by ≤ 10% without a related BCVA decrease by ≥ 10 letters; or ii) Maintain this interval if any of the following criteria is met: The CST value is reduced by> 10%; or The CST value is reduced by ≤ 10%, with associated BCVA reduction by ≥ 10 letters, or The CST value increased by more than 10% and less than 20%, and there is no related BCVA decreased by more than 5 letters; iii) If any of the following criteria is met, the interval is shortened by 4 weeks: The CST value increased by> 10% and ≤ 20%, with associated BCVA decrease by ≥ 5 to <10 letters, or The CST value increased by> 20% without a related decrease in BCVA by ≥ 10 letters; or The CST value increased by ≤ 10%, and the associated BCVA decreased by ≥ 10 letters; iv) In the following cases, the interval is shortened to Q4W The CST value increased by> 10%, and the associated BCVA decreased by ≥ 10 letters. Such as the method of any one of claim 20, 21 or 22, which further comprises: Receive updated patient data in the computing system; Use the computing system to continuously update or maintain the dosing interval based on the updated patient data; and Based on the updated or maintained dosing interval, a visualized result, user interface, or notification is generated. A use of personalized dosing schedule based on personalized treatment interval (PTI) (for nAMD), where the computing system obtains the PTI by: Receive patient data in the computing system, the patient data includes the patient's CST and best corrected visual acuity (BCVA), as well as optional information about the assessment of new macular hemorrhage; and Extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; among them a) When all the following criteria are met, the interval is extended by 4 weeks (to the maximum Q16W): i) Compared with the average value of the last two study drug administration visits, CST is stable. Stability is defined as the change of CST less than 30 µm and compared with the lowest measured value of the drug administration visit in the study, CST No increase ≥ 50 µm, ii) Compared with the average of the last two study drug administration visits, BCVA did not decrease by ≥ 5 letters, and compared with the highest study drug administration visit measurement value, BCVA did not decrease by ≥ 10 letters , iii) No new macular hemorrhage b) the interval In the case of meeting one of the following criteria, shorten 4 weeks (to a minimum of Q8W), or In the event that two or more of the following criteria are met or one criterion includes new macular hemorrhage, shorten the interval to 8 weeks: i) Compared with the average of the last two dosing visits, the CST increased by ≥ 50 µm, or compared with the lowest dosing visit measurement value, the CST increased by ≥ 75 µm; ii) Compared with the average of the last two dosing visits, the BCVA decreased by ≥ 5 letters, or compared with the highest dosing visit measurement value, the BCVA decreased by ≥ 10 letters; iii) New macular hemorrhage. A use of personalized dosing schedule based on personalized treatment interval (PTI) (for DME), where the computing system obtains the PTI by: Receive patient data, which includes the patient's CST and best corrected visual acuity (BCVA); and Extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; among them i) In the following cases, the interval is extended by 4 weeks, The CST value increases or decreases by ≤ 10%, and there is no related BCVA decrease by ≥ 10 letters; ii) Maintain this interval in the following cases: The CST is reduced by> 10%, or The CST value increases or decreases by ≤ 10%, and the associated decrease in BCVA is ≥ 10 letters, or The CST value increased by more than 10% and less than 20%, and there is no related BCVA decreased by more than 5 letters; iii) In the following cases, the interval is shortened by 4 weeks The CST value increased by> 10% and ≤ 20%, with associated BCVA decrease by ≥ 5 to <10 letters; or The CST value increased by ＞ 20%, and there was no related BCVA decrease by ≥ 10 letters; iv) In the case where the CST value increases> 10%, and the associated BCVA decreases ≥ 10 letters, the interval is shortened by 8 weeks. A use of personalized dosing schedule based on personalized treatment interval (PTI) (for macular edema secondary to central retinal vein occlusion, secondary to semi-retinal vein occlusion or secondary to branch vein occlusion), which is calculated The system obtains the PTI through the following: Receive patient data, which includes the patient's CST and best corrected visual acuity (BCVA); and Extend, shorten or maintain the dosing interval based on the received patient data compared with the respective reference CST and BCVA; among them i) In the following cases, the interval is extended by 4 weeks The CST value increased or decreased by ≤ 10% without a related BCVA decrease by ≥ 10 letters; or ii) Maintain this interval if any of the following criteria is met: The CST value is reduced by> 10%; or The CST value is reduced by ≤ 10%, with associated BCVA reduction by ≥ 10 letters, or The CST value increased by more than 10% and less than 20%, and there is no related BCVA decreased by more than 5 letters; iii) If any of the following criteria is met, the interval is shortened by 4 weeks: The CST value increased by> 10% and ≤ 20%, with associated BCVA decrease by ≥ 5 to <10 letters, or The CST value increased by> 20% without a related decrease in BCVA by ≥ 10 letters; or The CST value increased by ≤ 10%, and the associated BCVA decreased by ≥ 10 letters; iv) In the following cases, the interval is shortened to Q4W The CST value increased by> 10%, and the associated BCVA decreased by ≥ 10 letters.

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